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Autophagy [JOURNAL]

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MOTS-c, a mitochondrial-derived peptide, ameliorates lysosomal membrane permeability and improves survival of soft tissue transplantation.

Shi J, Wu Y, Liu X … +16 more , Xia W, Wu J, Lou J, Zhang X, Zhang J, Yang N, Chi W, Xiang L, Zhang Y, Shu Y, Miao R, Zhao J, Zhu X, Qi J, Xiao J, Zhou K

Autophagy · 2026 Jun · PMID 42153537 · Publisher ↗

Distal ischemic necrosis remains a major challenge in reconstructive surgery. Mitochondria and lysosomes interact via signaling and membrane contacts to maintain cellular homeostasis. Mitochondrial-derived peptide MOTS-c... Distal ischemic necrosis remains a major challenge in reconstructive surgery. Mitochondria and lysosomes interact via signaling and membrane contacts to maintain cellular homeostasis. Mitochondrial-derived peptide MOTS-c, encoded by the rRNA open reading frame, enhances mitochondrial function by reducing reactive oxygen species (ROS) and stabilizing the membrane potential, potentially preserving lysosomal integrity and reducing lysosomal membrane permeabilization (LMP). This study investigated the protective effects and underlying mechanisms of MOTS-c in ischemic flaps. RNA sequencing explored MOTS-c mechanisms in ischemic flaps. Tissue clearing, laser speckle contrast imaging and Doppler analyses revealed improved blood flow perfusion following MOTS-c treatment. Histological staining (HE, Masson, F-CHP) demonstrated enhanced angiogenesis and collagen remodeling. Western blotting, ELISA, and immunofluorescence were used to assess pyroptosis, macroautophagy/autophagy, LMP, and MAPK1/ERK2-MAPK3/ERK1-NFKB/NF-κB pathway-related proteins. MOTS-c reduced endothelial pyroptosis, enhanced autophagy, and attenuated LMP in ischemic flaps. Mechanistically, overexpression of PLA2G4A/cPLA2 (phospholipase A2, group IVA (calcium, calcium dependent)) via AAV confirmed that MOTS-c enhances autophagy and reduces pyroptosis and LMP by suppressing PLA2G4A phosphorylation. Furthermore, MOTS-c inhibited PLA2G4A via the MAPK1-MAPK3-NFKB signaling cascade, thereby reducing LMP and enhancing flap survival. These findings suggest that MOTS-c restores cellular homeostasis by targeting the PLA2G4A-LMP axis, representing a promising therapeutic strategy for improving outcomes in ischemic flap surgery. AA = arachidonic acid, AAV = adeno-associated virus, ACTA2/α-SMA = actin alpha 2, smooth muscle, aorta, ALs = autolysosomes, BECN1 = beclin 1, CASP1 = caspase 1, CQ = chloroquine, CTSB = cathepsin B, CTSD = cathepsin D, CTSL = cathepsin L, Co-IP = co-immunoprecipitation, DEGs = differentially expressed genes, ELISA = enzyme-linked immunosorbent assay, F-CHP = 5-FAM-conjugated collagen hybridizing peptide staining, GSDMD = gasdermin D, GO = gene Ontology, GPT/ALT = glutamic pyruvic transaminase, soluble, GOT1/AST = glutamic-oxaloacetic transaminase 1, soluble, HE = hematoxylin-eosin, HUVECs = human umbilical vein endothelial cells, IP/MS = immunoprecipitation coupled with mass spectrometry, IL1B/IL-1β = interleukin 1 beta, IL18 = interleukin 18, IP = intraperitoneal injection, IV = intravenous injection, LDBF = laser Doppler blood flow, LMP = lysosomal membrane permeability, MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3, MAPK = mitogen-activated protein kinase, NAGLU = alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB), NFKB/NF-κB = nuclear factor kappa B, NLRP1 = NLR family pyrin domain containing 1, NLRP3 = NLR family pyrin domain containing 3, PECAM1/CD31 = platelet/endothelial cell adhesion molecule 1, PLA2G4A/cPLA2 = phospholipase A2, group IVA (cytosolic, calcium-dependent), PYCARD/ASC = PYD and CARD domain containing, PIK3C3/VPS34 = phosphatidylinositol 3-kinase catalytic subunit type 3, PMA = phorbol 12-myristate 13-acetate, ROS = reactive oxygen speciesSQSTM1/p62 = sequestosome 1, SPR = surface plasmon resonance, scRNA-seq = single-cell RNA sequencing, UMAP = uniform manifold approximation and projection, WB = western blotting.
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Organelle contact reorganization drives calcium-dependent autophagy under proteostatic stress.

Ko Y, Ko M, Ueffing M … +2 more , Kang HJ, Kwon HJ

Autophagy · 2026 Jun · PMID 42152515 · Publisher ↗

Disruption of proteostasis is a defining feature of cancer and other chronic diseases. The AAA+ ATPase VCP/p97 (valosin containing protein) is a key regulator of proteostasis by disassembling ubiquitinated substrates for... Disruption of proteostasis is a defining feature of cancer and other chronic diseases. The AAA+ ATPase VCP/p97 (valosin containing protein) is a key regulator of proteostasis by disassembling ubiquitinated substrates for degradation. VCP overexpression supports cancer cell survival and correlates with poor prognosis, promoting the development of VCP inhibitors as anti-cancer agents. However, the molecular basis for cancer-selective vulnerability of VCP inhibition remains unclear. Here, we demonstrate that allosteric VCP inhibition triggers cell-type specific macroautophagy/autophagy through dynamic reorganization of organelle contact sites. In human umbilical vein endothelial cells (HUVECs), VCP inhibition induces adaptive autophagy through coordinated reorganization of plasma membrane (PM)-ER-mitochondria contacts. Controlled opening of the mitochondrial permeability transition pore (mPTP) releases calcium into the cytosol, activating AMP-activated protein kinase (AMPK) and TFEB pathways, collectively enhancing autophagic flux and sustaining endothelial survival. Critically, calcium-activated kinase inhibitor or calcium chelators blocked VCP inhibitor-induced autophagy in HUVECs, confirming calcium signaling as the central mediator of adaptive autophagy. In contrast, HCT116 colon cancer cells fail to maintain calcium homeostasis under VCP inhibition, leading to mitochondrial calcium overload, defective autophagy, and cell death. Together, our findings identify organelle contact reorganization and calcium homeostasis as key determinants of cell fate under conditions of proteotoxic stress, revealing how VCP inhibition selectively suppresses tumor progression while preserving vascular integrity that could enhance drug delivery and reduce tumor hypoxia.: ATF4: activating transcription factor 4; ATG3: autophagy related 3; ATG7: autophagy related 7; ATP: adenosine triphosphate; CAMKK2: calcium/calmodulin dependent protein kinase 2; CETSA: cellular thermal shift assay; CQ: chloroquine; CTS: cryptotanshinone; DDIT3/CHOP: DNA damage inducible transcript 3; DQ-BSA: dye quenched-bovine serum albumin; EIF2A: eukaryotic initiation factor 2A; ER: endoplasmic reticulum; ERAD: endoplasmic reticulum-associated protein degradation; HCT116: human colon carcinoma cell line; HSPA5: heat shock protein family A (Hsp70) member 5; HUVECs: human umbilical vein endothelial cells; ITPR1/IPR1: inositol 1,4,5-trisphosphate receptor type 1; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; mPTP: mitochondrial permeability transition pore; MT-ND1: mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1; MTOR: mechanistic target of rapamycin kinase; ORAI1: ORAI calcium release-activated calcium modulator 1; PLA: proximity ligation assay; PM: plasma membrane; PRKAA/AMPK: protein kinase AMP-activated catalytic subunit alpha; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; STIM1: stromal interaction molecule 1; TFEB: transcription factor EB; U87MG: human glioblastoma astrocytoma cell line; FAF2/UBXD8: Fas associated factor family member 2; UPR: unfolded protein response; VCP/p97: valosin containing protein; VDAC1: voltage dependent anion channel 1.
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Thr308-dephosphorylated AKT1 licenses SQSTM1-LC3C-mediated antiviral autophagy.

Hu Z, Lin L, Zhong Y … +5 more , Li C, Li Y, Wu H, Zhou J, Hu B

Autophagy · 2026 May · PMID 42152503 · Publisher ↗

AKT1 is classically known as a serine/threonine kinase controlling cell survival and proliferation, yet its kinase-independent functions remain poorly understood. Here we show that recognition of dsRNA viral capsids by m... AKT1 is classically known as a serine/threonine kinase controlling cell survival and proliferation, yet its kinase-independent functions remain poorly understood. Here we show that recognition of dsRNA viral capsids by membrane-associated HSP90AA1 disrupts the HSP90-AKT1 interaction, inducing AKT1 dephosphorylation at Thr308. This non-phosphorylated AKT1 acts as a scaffold to recruit PDPK1 and SQSTM1, enabling PDPK1-dependent phosphorylation of SQSTM1 at Ser349 and selective loading of viral capsids into LC3C-positive phagophores for degradation. An IBDV capsid mutant defective in SQSTM1 binding escapes this pathway. In vivo, expression of non-phosphorylatable AKT1 suppresses rotavirus replication in a SQSTM1-dependent manner. These findings identify an HSP90-initiated, kinase-independent AKT1 signaling axis that licenses antiviral macroautophagy/autophagy. AKT1: AKT serine/threonine kinase 1; CQ: chloroquine; dpi: days post-infection; dsRNA: double-stranded RNA; GABARAPL1: GABA type A receptor associated protein like 1; hpi: hour post infection; HSP90AA1: heat shock protein 90 alpha family class A member 1; IBDV: infectious bursal disease virus; KO: knockout; LIR: LC3-interacting region; MAP1LC3C/LC3C: microtubule associated protein 1 light chain 3 gamma; MOI: multiplicity of infection; PDPK1: 3-phosphoinositide dependent protein kinase 1; rVP2: recombinant His-tagged VP2; rVP4: recombinant His-tagged VP4; RV: rotavirus; SQSTM1: sequestosome 1; WT: wild-type.
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Influenza a virus NS2 suppresses NFKB/NF-κB signaling to facilitate viral replication by mediating the autophagic-degradation of IKBKG/NEMO.

Zhang B, Han L, Cui C … +4 more , Huang J, Zhu Q, Lei C, Xu S

Autophagy · 2026 May · PMID 42152489 · Publisher ↗

Influenza A virus (IAV) is an important zoonotic pathogen responsible for substantial respiratory morbidity and mortality. Elucidating the mechanisms by which IAV evades host innate immunity is critical for developing no... Influenza A virus (IAV) is an important zoonotic pathogen responsible for substantial respiratory morbidity and mortality. Elucidating the mechanisms by which IAV evades host innate immunity is critical for developing novel antiviral strategies. Although the IAV non-structural protein 2 (NS2) is well-characterized for the export of viral ribonucleoproteins (vRNPs) from the host cell nucleus, the function of NS2 in evading host innate immunity, especially the NFKB/NF-κB (nuclear factor kappa B) signaling pathway, remains poorly understood. The present study uncovered that NS2 is a novel viral inhibitor of the NFKB pathway. Mechanistically, NS2 interacted with and mediated the degradation of the NFKB essential modulator (IKBKG/NEMO), thereby suppressing downstream signal transduction. The macroautophagy/autophagy receptor OPTN (optineurin) was exploited by NS2 to mediate the selective autophagic degradation. Furthermore, the K72 residue was critical for the NS2-mediated degradation of IKBKG/NEMO, as the K72R substitution in NS2 disrupted the IKBKG/NEMO-NS2 interaction and abrogated the autophagic degradation. In addition, NS2 mutant virus displayed less viral load and milder pathogenicity in mice. In conclusion, these findings highlighted the novel biological function of IAV NS2 in exploiting selective autophagy to evade host defenses, and offered a potential target for controlling IAV infections.: 3-MA: 3-methyladenine; AIV: avian influenza virus; ATG7: autophagy related 7; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; co-IP: co-immunoprecipitation; CHUK/IKKα: component of inhibitor of nuclear factor kappa B kinase complex; DAPI: 4', 6-diamidino-2-phenylindole, dihydrochloride; dsRNA: double-stranded RNA; dpi: days post-infection; EID: 50% egg infective dose; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; hpi: hours post-infection; IAV: influenza A virus; IFN: interferon; IKBKB/IKKβ: inhibitor of nuclear factor kappa B kinase subunit beta; IFNG: interferon gamma; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase subunit gamma; IKK: IκB kinase; IP: immunoprecipitation; IRF3: interferon regulatory factor 3; IRF7: interferon regulatory factor 7; LAMP1: lysosome associated membrane protein 1; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K14/NIK: mitogen-activated protein kinase kinase kinase 14; MAVS: mitochondrial antiviral signaling protein; MLD: 50% mouse lethal dose; MOI: multiplicity of infection; MRV/Sendai virus: murine respirovirus; NBR1: NBR1 autophagy cargo receptor; NEP: nuclear export protein; NFKB/NF-κB: nuclear factor kappa B; NFKB2/p100: nuclear factor kappa B subunit 2; NFKBIA/IκBα: NFK inhibitor alpha; NP: nucleoprotein; NS1: non-structural protein 1; OPTN: optineurin; PB1: basic polymerase 1; PBS: phosphate-buffered saline; poly(I:C): polyriboinosinic polyribocytidylic acid; PRRs: pattern recognition receptors; RELA/p65: RELA proto-oncogene, NF-kB subunit; RELB: RELB proto-oncogene, NF-kB subunit; RIGI: RNA sensor RIG-I; RIGI-IN: RIGI-CARD; RLR: RIGI-like-receptor; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SIM: SUMO-interacting motif; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TBK1: TANK binding kinase 1; TNF: tumor necrosis factor; TRAF6: TNF receptor associated factor 6; TOLLIP: toll interacting protein; Vec: empty vector; vRNP: viral ribonucleoprotein.
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USF2 restricts enterovirus replication and transmission by inhibiting autophagy and vesicle-mediated viral spread.

Liang T, Peng Z, Xi R … +5 more , Chen S, Yin G, Wang L, Wang T, Wei G

Autophagy · 2026 May · PMID 42152487 · Publisher ↗

Enteroviruses pose a substantial global health burden, and a complete understanding of host defense mechanisms is still evolving. Through proteomic profiling of coxsackievirus B3 (CVB3)-infected cells, we identified the... Enteroviruses pose a substantial global health burden, and a complete understanding of host defense mechanisms is still evolving. Through proteomic profiling of coxsackievirus B3 (CVB3)-infected cells, we identified the host factor USF2 (upstream transcription factor 2) as significantly upregulated, a process that may be associated with the viral capsid protein VP4. Here, we characterize USF2 as a novel, infection-induced restriction factor. Functional studies demonstrate that USF2 knockdown enhances viral RNA replication without affecting entry, while its overexpression suppresses replication and cytopathic effects. Mechanistically, USF2 acts as a transcriptional repressor of autophagy-related genes, thereby inhibiting autophagosome formation. Crucially, USF2 depletion promotes the release of MAP1LC3/LC3-positive extracellular vesicles carrying infectious virus, defining its role in blocking a key route of vesicle-mediated viral dissemination. USF2 exhibits broad antiviral activity against multiple enteroviruses and other RNA viruses that depend on cytoplasmic membrane remodeling. Our findings reveal that the host deploys a virus-triggered transcriptional regulator to restrict enterovirus spread by suppressing macroautophagy/autophagy-dependent viral dissemination. BafA1: bafilomycin A; CQ: chloroquine; CPE: cytopathic effect; CVB3: coxsackievirus B3; dpi: days post infection; DEGs: differentially expressed genes; EV-A71: enterovirus A71; EVs: extracellular vesicles; GFP: green fluorescent protein; LAMP1: lysosomal-associated membrane protein 1; TR: LysoTracker Red; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MOI: multiplicity of infection; TFEB: transcription factor EB; USF2: upstream transcription factor 2; UPR: unfolded protein response; VP1: viral capsid protein 1; VP4: viral capsid protein 4.
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FASN mediates crosstalk between autophagy and lipid metabolism via the AMPK-MTOR pathway in early age-related macular degeneration.

Cai J, Jiang Y, Liu X … +3 more , Yang T, Yang P, Chen L

Autophagy · 2026 May · PMID 42152481 · Publisher ↗

Age-related macular degeneration (AMD) involves sub-retinal pigment epithelium (sub-RPE) lipid deposition in the early stage, with dysregulated lipid metabolism and impaired macroautophagy/autophagy implicated, yet the m... Age-related macular degeneration (AMD) involves sub-retinal pigment epithelium (sub-RPE) lipid deposition in the early stage, with dysregulated lipid metabolism and impaired macroautophagy/autophagy implicated, yet the molecular mechanisms underlying their interaction remain unclear. In this study, transcriptomic analysis of human macular tissues identified FASN (fatty acid synthase), a regulator of lipid metabolism and lysosomal function, as a significantly upregulated key hub gene in early AMD. In mice fed a high-fat diet (HFD), retina-RPE-choroid complexes revealed elevated FASN alongside autophagy suppression, lysosomal dysfunction, and lipid accumulation. In vitro, FASN protein levels increased in RPE cells treated with the autophagy inhibitor 3-methyladenine (3-MA), but decreased with the autophagy activator rapamycin (RAPA), without transcriptional changes; lysosomal blockade with chloroquine (CQ) induced FASN accumulation, which was significantly delayed following autophagy inhibition. These findings indicate that FASN accumulation results from insufficient autophagic degradation. Conversely, FASN knockdown or pharmacological inhibition enhanced autophagic flux and promoted lysosomal lipid clearance in RPE cells. Mechanistically, FASN inhibition increased AMPK phosphorylation and decreased MTOR activity, thereby facilitating autophagy and lipophagy. Collectively, our findings reveal a self-amplifying pathological circuit in early AMD: autophagy impairment drives FASN accumulation, which in turn exacerbates lysosomal dysfunction and lipid accumulation. Targeting the FASN-AMPK-MTOR axis may offer a promising therapeutic strategy for early AMD.
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Byakangelicin alleviates metabolic dysfunction-associated steatohepatitis by selective inhibition of a non-canonical MTORC1 signaling pathway.

Du X, Fang Z, Liu G … +6 more , Wang L, Ju L, Gao W, Song Y, Lei L, Li X

Autophagy · 2026 May · PMID 42152469 · Publisher ↗

Metabolic dysfunction-associated steatohepatitis (MASH) is emerging as a leading cause of chronic liver disease. MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) is a potential therapeutic target, whereas... Metabolic dysfunction-associated steatohepatitis (MASH) is emerging as a leading cause of chronic liver disease. MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) is a potential therapeutic target, whereas suppression of total MTORC1 activity can lead to unwanted effects. Here, we found that byakangelicin (Bya), a natural compound, selectively inhibited MTORC1-mediated phosphorylation of TFEB (transcription factor EB), without affecting canonical MTORC1 substrates. Knockout of hepatic blocked the alleviation effects of Bya on hepatic steatosis, inflammation, insulin resistance, and fibrosis in mice, while reintroduction of TFEB restored these effects. We identified Bya directly bound to MET370 and PHE552 of FLCN (folliculin), suppressing the function of the FLCN-FNIP1 (folliculin interacting protein 1)/FNIP2 complex, which in turn inhibited MTORC1-mediated cytoplasmic sequestration of TFEB. Mutation of FLCN (M370A and F552A) in the liver abolished Bya-induced protection against MASH. Thus, Bya is a promising therapeutic natural compound for MASH, and selective inhibition of MTORC1 is a potential approach to treat this disease. aa, amino acids; AAV, adeno-associated virus; Bio, biotin; Bio-Bya, biotin-conjugated Bya; BSA, bovine serum albumin; BW, body weight; Bya, byakangelicin; CETSA, cellular thermal shift assay; CHIP-atlas, chromatin immunoprecipitation atlas; C, maximum concentration; CQ, chloroquine; DARTS; drug affinity responsive target stability assay; EIF4EBP1/4E-BP1, eukaryotic translation initiation factor 4E binding protein 1; FBS, fetal bovine serum; FDA, food and drug administration; FIMO-JASPAR, find individual motif occurrences-JASPAR; FLCN, folliculin; FNIP1, folliculin interacting protein 1; GAP, GTPase-activating protein; GOT1/AST, glutamic-oxaloacetic transaminase 1; GPT/ALT, glutamic-pyruvic transaminase; GTRD, gene transcription regulatory database; GTT, glucose tolerance test; H&E, hematoxylin and eosin; Hbonds, hydrogen bonds; HFD, high-fat diet; HFHC, high-fat and high-cholesterol; HOMA-IR, homeostatic model assessment of insulin resistance; HSCs, hepatic stellate cells; IP, immunoprecipitation; ITT, insulin tolerance test; K, dissociation constant; KEGG, kyoto encyclopedia of genes and genomes; KPBS, potassium phosphate-buffered saline; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LW/BW, liver-to-body weight ratio; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; MCD, methionine and choline deficient; MST, microscale thermophoresis assay; MTOR, mechanistic target of rapamycin kinase; MTORC1, MTOR complex 1; ND, normal diet; NFKB/NF-κB, nuclear factor kappa B; NFKBIA/IKBA, NFKB inhibitor alpha; OP, oleate acid and palmitate acid; PBS, phosphate-buffered saline; PCA, principal component analysis; qRT-PCR, real-time quantitative PCR; RELA/p65, RELA proto-oncogene, NF-kB subunit; Res, resmetirom; Rg, radius of gyration; RMSD, root-mean-square deviation; RMSF, root-mean-square fluctuation; RPS3, ribosomal protein S3; RPS6KB1/S6K1, ribosomal protein S6 kinase B1; RRAGC, ras related GTP binding C; SASA, solvent-accessible surface area; SNRPD2, small nuclear ribonucleoprotein D2 polypeptide; SQSTM1/p62, sequestosome 1; T, half-life; TFE3, transcription factor binding to IGHM enhancer 3; TFEB, transcription factor EB; TMEM192, transmembrane protein 192; VIM, vimentin; WT, wild-type.
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TRP53/p53 protects adult hippocampal neural stem cells from psychological stress by preventing autophagic cell death.

Jung S, Jeong H, Choe S … +9 more , Choi J, Chung KM, Kim JY, Lee E, Lee HW, Jeong Y, Kim EK, Sun W, Yu SW

Autophagy · 2026 May · PMID 42152468 · Publisher ↗

Psychological stress impairs adult hippocampal neurogenesis (AHN) and contributes to cognitive dysfunction. Previously, we reported that chronic psychological stress or the stress hormone corticosterone (CORT) induces au... Psychological stress impairs adult hippocampal neurogenesis (AHN) and contributes to cognitive dysfunction. Previously, we reported that chronic psychological stress or the stress hormone corticosterone (CORT) induces autophagic cell death (ACD) in adult hippocampal neural stem cells (ahNSCs). However, the regulatory mechanisms underlying this process remain largely unknown. The tumor suppressor gene is abundantly expressed in ahNSCs, yet its function under stress conditions has not been fully elucidated. Here, we demonstrate that, contrary to its well-established pro-apoptotic role, TRP53 acts as a survival factor that protects ahNSCs from stress-induced ACD. Conditional deletion of in neural stem cells heightened vulnerability to chronic restraint stress (CRS), resulting in worsened memory deficits and mood disturbances compared to wild-type controls. Mechanistically, CORT facilitated MAP1LC3/LC3-mediated autophagic degradation of TRP53 through its LC3-interacting region (LIR), thereby promoting ACD. However, overexpression of either wild-type TRP53 or a degradation-resistant LIR mutant suppressed ACD by interfering with the ATG14-containing PIK3C3/VPS34 complex. Moreover, treatment with RITA, a small-molecule activator of TRP53, disrupted the TRP53-LC3 interaction, stabilized TRP53 levels, and protected ahNSCs from ACD, ultimately preventing CRS-induced cognitive impairment in the hippocampus. These findings identify TRP53 as a key negative regulator of ACD in ahNSCs and suggest that TRP53-stabilizing small molecules could represent a novel class of antidepressant therapies by preserving AHN.: ahNSC: adult hippocampal neural stem cell; AHN: adult hippocampal neurogenesis; ACD: autophagic cell death; BafA1: bafilomycin A; ACTB actin, beta; CRS chronic restraint stress; c.CASP3: cleaved caspase 3; cKO conditional knockout; CORT: corticosterone; DG: dentate gyrus; i.p: intraperitoneal; KO: knockout; LABORAS: Laboratory Behavior Observation Registration and Analysis System; LIR LC3-interacting region; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MDM2: MDM2 proto-oncogene; NSC: neural stem cell; PFA: paraformaldehyde; PLA: proximity ligation assay; RITA: reactivation of TRP53 and induction of tumor cell apoptosis; SGK: serum/glucocorticoid regulated kinase; SGZ: subgranular zone; STS: staurosporine; TAM: tamoxifen; TRP53: transformation related protein 53; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; UVRAG: UV radiation resistance associated.
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Identification of a conserved receptor for degrading ribosomes through autophagy.

Govind CK, Klionsky DJ

Autophagy · 2026 Jun · PMID 42148801 · Full text

Ribosomes consist of approximately 80 distinct ribosomal proteins and rRNA. The genes encoding these ribosomal components are among the most highly expressed in growing cells. Changes in ribosome composition, such as tho... Ribosomes consist of approximately 80 distinct ribosomal proteins and rRNA. The genes encoding these ribosomal components are among the most highly expressed in growing cells. Changes in ribosome composition, such as those induced by oxidative stress, may compromise ribosome function. Such ribosomes are subsequently targeted for degradation. Additionally, under stress, both protein synthesis and ribosome biogenesis are downregulated. Under starvation stress, excess ribosomes are degraded through a process called ribophagy, a selective form of macroautophagy/autophagy that utilizes the autophagy pathway. While receptors for several selective autophagy pathways are known, the evolutionarily conserved ribophagy receptor was not identified until recently. In a recent publication, the authors identify Rpl12 and its homologs as receptors that promotes ribophagy from yeast to humans. They also demonstrate that ribophagy enhances lifespan and facilitates the clearance of pathogenic bacteria. AIM: Atg8-family interacting motif; ATG: autophagy related; LIR: LC3-interacting region; NUFIP1: nuclear FMR1 interacting protein 1.
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Peptide-mediated inhibition of aberrant chaperone-mediated autophagy in pericytes prevents glioblastoma progression through MAPT/tau secretion.

Salinas MD, Martínez IM, Naranjo E … +4 more , Molina ML, Cuervo AM, Muller S, Valdor R

Autophagy · 2026 May · PMID 42148707 · Publisher ↗

Glioblastoma (GB) is the most aggressive brain cancer, with poor prognosis due to infiltrative invasion of glioma stem cells (GSCs) and the immunosuppressive tumor microenvironment (TME). We have previously demonstrated... Glioblastoma (GB) is the most aggressive brain cancer, with poor prognosis due to infiltrative invasion of glioma stem cells (GSCs) and the immunosuppressive tumor microenvironment (TME). We have previously demonstrated that pericytes (PCs), specialized cells in the blood microvessels surrounding GB, are conditioned by infiltrating tumor cells to aberrantly upregulate their chaperone-mediated autophagy (CMA). Elevated CMA in PCs promotes stable cell-cell interactions with tumor cells and a pro-tumoral immune phenotype that supports tumor progression. In this work, to test if inhibition of CMA in PCs might be an effective strategy to reduce tumor survival, we have used the phosphopeptide P140, known to restore aberrant CMA upregulation in specific immune cells. We found that administration of P140 peptide in an immunocompetent GB mouse model with both patient-derived GSCs and GB cell lines, neutralizes GB-induced PC CMA upregulation resulting in ablation of PC-tumor cell interactions and triggering of a secretome toxic to tumor cells. We identified MAPT/tau, a known CMA substrate, as one of the main components of this secretome, and discovered that CMA-dependent PC MAPT/tau secretion within the GB TME plays a key role in cancer progression and recurrence. Furthermore, we found that perivascular accumulation of MAPT/tau is an effective way to monitor peptide P140 treatment efficacy in GB and for prognosis of the patient evolution. Our findings validate P140 peptide treatment as a safe and specific strategy to halt GB progression and establish the clinical relevance of extracellular MAPT/tau as a biomarker for therapeutic success in GB.: ACTA2/ASMA: actin alpha 2, smooth muscle; BBB: blood-brain barrier; CMA: chaperone-mediated autophagy; CTLA4: cytotoxic T-lymphocyte associated protein 4; DAB: 3-3'diaminobenzidine; GB: glioblastoma; PC: GB-conditioned pericyte; GSCs: glioblastoma stem cells; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; LAMP2A: lysosome associated membrane protein 2A; LI: lysosomal inhibitors; MAPT/tau: microtubule associated protein tau; NAc: N-acetylcysteine; PC: pericyte; PCGB: pericyte-glioblastoma coculture; PDGFRB: platelet derived growth factor receptor beta; ROS: Reactive oxygen species; SPARC: secreted protein acidic and cysteine rich; TME: tumor microenvironment; TNT: tunneling nanotubes.
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PTK2/FAK inhibition triggers TMED9-mediated protective autophagy in pancreatic cancer cell via enhancing ERGIC-ERES contact.

Wu MY, Tang W, Zhang XW … +10 more , Zhang MN, Xu HD, Yu SR, Cheng Y, Li L, Chen Y, Liang S, Pan Q, Lu JH, Chai J

Autophagy · 2026 May · PMID 42144738 · Publisher ↗

Macroautophagy/autophagy represents a promising therapeutic target in oncology, exhibiting context-dependent roles in tumor progression. Kinase inhibitors are a large group of anti-cancer drugs, and elucidating the regul... Macroautophagy/autophagy represents a promising therapeutic target in oncology, exhibiting context-dependent roles in tumor progression. Kinase inhibitors are a large group of anti-cancer drugs, and elucidating the regulatory effects of different kinase inhibitors on autophagy offers a valuable strategy to advance our understanding of autophagy regulation in cancer and develop innovative anti-cancer therapies. In this study, we developed a drug screening platform and performed high-content screening using a kinase inhibitor library. The screening identified PTK2/FAK (protein tyrosine kinase 2) inhibitors as potent autophagy inducers. Mechanistic investigations revealed that PTK2/FAK inhibition triggers rapid autophagic flux through a non-classical mechanism dependent on PTK2/FAK expression, which is associated with the spatial redistribution of ER exit sites (ERES). Further analysis demonstrated that PTK2/FAK inhibitor (FAKi)-induced ERES-associated autophagy is not contingent upon full PREB/SEC12 and SEC16 expression, but is sensitized to TMED9 expression level. Additionally, we identified AKAP13 as a novel FAKi-responsive protein that undergoes dephosphorylation upon FAKi treatment and contributes to TMED9-mediated ERES-associated autophagy. Given that ERES-associated autophagy is initiated through membrane contact between ERES and the ER-Golgi intermediate compartment (ERGIC), we further observed enhanced TMED9-ERGIC interactions following FAKi treatment. Furthermore, functional studies confirmed that FAKi-induced autophagy promotes pancreatic ductal adenocarcinoma (PDAC) cell survival both and . Collectively, our work unveils a previously unrecognized mechanism of FAKi-mediated autophagy induction and provides new insights for developing targeted therapies against PDAC. AKAP13: A-kinase anchoring protein 13; AMPK: AMP-activated protein kinase; BAF: bafilomycin A1; ECM: extracellular matrix; ER: endoplasmic reticulum; ERES: endoplasmic reticulum exit sites; ERGIC: ER-Golgi intermediate compartment; GSK: GSK2256098; MTOR: mechanistic target of rapamycin kinase; PDAC: pancreatic ductal adenocarcinoma; PI3K: phosphoinositide 3-kinase; PI4KB: phosphatidylinositol 4-kinase beta; PTK2/FAK: protein tyrosine kinase 2; TMED9: transmembrane p24 trafficking protein 9; ULK1: unc-51 like autophagy activating kinase 1.
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Dual mechanism of human ATG10S in suppressing MEF2A-Driven pro-inflammatory responses.

Zhang MQ, Wang ZH, Zhang JP

Autophagy · 2026 May · PMID 42144735 · Publisher ↗

Cytokine storm, characterized by excessive release of pro-inflammatory cytokines, contributes to the severity and exacerbation of various diseases. Current therapies targeting individual cytokines prove inadequate due to... Cytokine storm, characterized by excessive release of pro-inflammatory cytokines, contributes to the severity and exacerbation of various diseases. Current therapies targeting individual cytokines prove inadequate due to the complex and multifactorial nature of inflammatory cascades. Here, we report human ATG10S, a novel isoform of the autophagy-related protein ATG10, as a potential inhibitor of cytokine storms. Using SARS-CoV-2 Spike (S) protein- or LPS-induced pro-inflammatory zebrafish and co-cultured human cell models, we found that ATG10S significantly reduced the expression of key pro-inflammatory cytokines (IFNA, IFNG, IL1B, IL6, TNF/TNFA, IL8, and CCL2), all transcriptionally regulated by MEF2A (myocyte enhancer factor 2A). Mechanistically, ATG10S bound directly to MEF2A at residues D61/D63, facilitating its selective autolysosomal degradation through MAP1LC3B/LC3B interaction, while it also competed with MAPK7/ERK5 for MEF2A binding to disrupt the TLR4-MAPK7-MEF2A signaling axis. This dual mechanism reduced both MEF2A protein levels and transcriptional activity, thereby attenuating cytokine overproduction. Importantly, ATG10S restored autophagic flux impaired by inflammatory stimuli and exhibited high specificity, sparing unrelated transcription factors. These findings established MEF2A as a critical regulator of the cytokine storm and revealed ATG10S as a distinctive macroautophagy/autophagy-linked immunomodulator that integrated selective autophagic degradation and transcriptional interference. Our study provides mechanistic insight into autophagy-mediated inflammatory regulation and highlights ATG10S as a promising therapeutic candidate for cytokine storm-associated diseases.: ATG: autophagy related; co-IP: co-immunoprecipitation; CQ: chloroquine; dpf: days post-fertilization; ELISA: enzyme-linked immunosorbent assay; hpi: hours post-injection; LC3B: microtubule-associated protein 1 light chain 3 beta; LIR: LC3-interacting region; LPS: lipopolysaccharide; MAPK7/ERK5: mitogen-activated protein kinase 7; MDMs: macrophages; MEF2A: myocyte enhancer factor 2A; MO: morpholino; S: spike protein; SQSTM1: sequestosome 1; TLR4: toll like receptor 4.
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PPARG activation by pioglitazone promotes mitophagy and inhibits the NLRP3 inflammasome to alleviate arthritic joint inflammation and bone damage.

Fu T, Wu Y, Wang B … +5 more , Zhang Q, Guo L, Han Z, Cao J, Lin J

Autophagy · 2026 May · PMID 42144710 · Publisher ↗

Rheumatoidarthritis (RA) is an autoimmune disease accompanied by joint swelling,stiffness, and pain, leading to a sharp decline in quality of life. However,the treatment of RA still faces numerous challenges. Clinical st... Rheumatoidarthritis (RA) is an autoimmune disease accompanied by joint swelling,stiffness, and pain, leading to a sharp decline in quality of life. However,the treatment of RA still faces numerous challenges. Clinical studies indicatethat specific hypoglycemic agents alleviate the symptoms of RA, while the potentialmolecular mechanism remains unknown. Herein, we initially assess the efficacyof various categories of anti-diabetic medications including biguanides, GLP1R(glucagon like peptide 1 receptor) agonists, SLC5A2/SGLT2 (solute carrierfamily 5 member 2) inhibitors, DPP4 (dipeptidyl peptidase 4) inhibitors,sulfonylureas, thiazolidinediones, and insulin analog in RA models ofcollagen-induced arthritis (CIA) and serum-transfer arthritis (STA). Resultsdemonstrate that solely thiazolidinediones (pioglitazone [PIOG]) confersuperior efficacy, whereas the other anti-diabetic agents provide minimal or notherapeutic benefits. Mechanistically, thiazolidinediones (PIOG) activatesPPARG/PPARγ (peroxisome proliferator activated receptor gamma) to promotemitophagic flux, thereby inhibiting aberrant NLRP3 inflammasome activation andreducing pro-inflammatory factors IL1B/IL1-BETA (interleukin 1 beta) and IL18 (interleukin18) release. Notably, loss of autophagy either genetically or pharmacologicallysubstantially diminishes the anti-inflammatory effects of PIOG both in vitroand in vivo. In summary, these results offer new mechanistic insight intodisease crosstalk and support the translational value of thiazolidinedionesPIOG as a candidate for precision therapy in RA or multimorbidity of RA and type2 diabetes mellitus (T2DM). 3-MA: 3-methyladenine; ACP5/TRAP: acid phosphatase 5, tartrate resistant; AIM2: absent in melanoma 2; ALUM: aluminum hydroxide adjuvant; ANOVA: analysis of variance; PYCARD/ASC: PYD and CARD domain containing; ATP: adenosine triphosphate; BMDM: bone marrow-derived macrophage; BV:TV: bone volume:tissue volume; CIA: collagen-induced arthritis; DAPI: 4',6-diamidino-2-phenylindole; DNA: deoxyribonucleic acid; ELISA: enzyme-linked immunosorbent assay; FG: Fast Green; GFP: green fluorescent protein; GSDMD: gasdermin D; IL1B/IL1-BETA: interleukin 1 beta; IL18: interleukin 18; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; Micro-CT: micro-computed tomography; MSU: monosodium urate; mtDNA: mitochondrial DNA; mtROS: mitochondrial reactive oxygen species; NAC: N-acetylcysteine; NLRP1B: NLR family, pyrin domain containing 1B; NLRP3: NLR family, pyrin domain containing 3; NLRC4: NLR family, CARD domain containing 4; OGTT: oral glucose tolerance test; PBS: phosphate-buffered saline; PINK1: PTEN induced putative kinase 1; PIOG: pioglitazone; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; RA: rheumatoid arthritis; ROS: reactive oxygen species; STA: serum transfer arthritis; STZ: streptozotocin; T2DM: type 2 diabetes mellitus; Tb.N: trabecular number; Tb.Sp: trabecular separation; Tb.Th: trabecular thickness; THP-1: human monocytic leukemia cell line; TNF/TNF-α: tumor necrosis factor; TOMM20: translocase of outer mitochondrial membrane 20.
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African swine fever virus I10L protein inhibits autolysosome formation by disrupting RAB7-HOPS complex-dependent SNARE complex assembly.

Chen M, Sunkang Y, Cheng T … +7 more , Liu L, Li H, Yuan H, Huang L, Sun L, Qi W, Shang Y

Autophagy · 2026 May · PMID 42138513 · Publisher ↗

Macroautophagy/autophagy serves as a crucial cellular defense mechanism against invading pathogens. However, viruses have evolved diverse strategies to evade or even exploit autophagy for their own replication. In this s... Macroautophagy/autophagy serves as a crucial cellular defense mechanism against invading pathogens. However, viruses have evolved diverse strategies to evade or even exploit autophagy for their own replication. In this study, we reveal that the African swine fever virus (ASFV)-encoded I10L protein suppresses autophagy by blocking autophagosome-lysosome fusion. Mechanistically, I10L directly interacts with the endolysosomal RAB GTPase RAB7, a master regulator of vesicle docking at late endosomes and lysosomes. This interaction competitively prevents RAB7 from binding to VPS39, a core component of the homotypic fusion and vacuole protein sorting (HOPS) complex. Consequently, I10L disrupts the assembly of the STX17-SNAP29-VAMP8 SNARE complex, which is essential for autophagosome-lysosome fusion. ASFV infection thus induces autophagosome accumulation, whereas I10L deletion reverses this effect and attenuates viral replication in primary macrophages. Our findings uncover a novel immune evasion strategy by which ASFV subverts lysosomal degradation through RAB7-HOPS axis manipulation, providing both mechanistic insights into viral pathogenicity and potential therapeutic targets for antiviral development. ASFV: African swine fever virus; GEF: guanine nucleotide exchange factor; GFP: green fluorescent protein; HOPS: homotypic fusion and vacuole protein sorting; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PAMs: primary alveolar macrophages; RAB7: RAB7, member RAS oncogene family; siRNA: small interfering RNA; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TM: transmembrane domain; VAMP8: vesicle associated membrane protein 8; VPS39: VPS39 subunit of HOPS complex; VPS41: VPS41 subunit of HOPS complex; YKT6: YKT6 vesicular SNARE protein.
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Formation and function of a novel Atg21-retromer complex in .

Strubel N, Förster J, Kramer F … +1 more , Thumm M

Autophagy · 2026 May · PMID 42135947 · Publisher ↗

Atg18, Atg21 and Hsv2 are homologous proteins that fulfill macroautophagic/autophagic and non-autophagic functions. We now found that Atg21 interacts with Pep8/Vps26, Vps29 and Vps35, the components of the cargo selectiv... Atg18, Atg21 and Hsv2 are homologous proteins that fulfill macroautophagic/autophagic and non-autophagic functions. We now found that Atg21 interacts with Pep8/Vps26, Vps29 and Vps35, the components of the cargo selective complex of the retromer. We identified Atg21 residues required for retromer binding and focused on two of them. The first, T106, is part of an STS-motif, which also mediates Atg18-binding to the retromer, while in Hsv2 this motif is not conserved. As a second retromer binding residue, we identified D28 of Atg21. Interestingly, the corresponding D45 of Hsv2 also confers retromer binding, but the analogous E34 of Atg18 does not. Together, Atg18 uses binding residue 1, while Atg21 uses 1 and 2 and Hsv2 only 2. During autophagy, Atg21 organizes the Atg8-lipidation machinery by interacting with Atg16 via the bottom side of its β-propeller. Partial overlap between the Atg16 binding residues and the retromer binding residues indicates mutually exclusive interaction. Indeed, lack of Atg16 enhances Atg21 binding to the retromer. The Atg21-retromer shows vacuole fission activity, which requires both retromer binding residues and the membrane-bending activity of its loop 6 C/D. Additionally, overexpression of Atg21 led to mislocalization of the Prc1/carboxypeptidase Y cargo receptor Pep1/Vps10 from the Golgi to Vps17-positive endosomes and to Prc1 secretion. We detected a cross-talk among the different retromer complexes. In the absence of the canonical retromer component Vps5, more Atg21-retromer complexes were formed. Furthermore, the vacuole hyper-fragmentation of cells cooperatively required Atg18 and Atg21. Along this line, we found that Atg21 interacts with Atg18 and Hsv2. Atg: autophagy related, CSC: cargo specific complex (of the retromer), PAS: phagophore assembly site, Prc1/CPY/carboxypeptidase Y: proteinase C, PROPPIN: beta-propeller that binds phosphoinositides.
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The autophagic and non-autophagic functions of the PROPPIN Hsv2.

Taylor MF, Foerster J, Kramer F … +2 more , Strubel N, Thumm M

Autophagy · 2026 May · PMID 42135946 · Publisher ↗

Autophagosome formation depends on PtdIns3P, its presence is deciphered by PROPPINs, a family of β-propellers, which in yeast consists of Atg18, Atg21 and Hsv2 and in mammals of WIPI1, WIPI2, WDR45B/WIPI3 and WDR45/WIPI4... Autophagosome formation depends on PtdIns3P, its presence is deciphered by PROPPINs, a family of β-propellers, which in yeast consists of Atg18, Atg21 and Hsv2 and in mammals of WIPI1, WIPI2, WDR45B/WIPI3 and WDR45/WIPI4. While Atg18 is required for scaffolding the Atg2-Atg9 complex, which mediates non-vesicular membrane transport to the phagophore, Atg21 organizes the Atg8 lipidation machinery. Atg18 further acts as part of a retromer complex in vacuole fragmentation. So far, the function of Hsv2 remained elusive. Here we show that Hsv2 is required for autophagy of large cargos such as the fatty acid synthase complex (FAS) and ribosomes. We further found that Hsv2 interacts with the key retromer component Vps35 and mediates vacuole fission cooperatively with Atg18. Interestingly, the residues for interaction of Hsv2 with Atg2 and Vps35 are distinct from those of Atg18. Hsv2 is known to affect the biogenesis of the spore wall, which prompted us to include diploid cells in our analyses. We found that Hsv2 interacts with the SNARE Pep12, and that Pep12 mislocalized to the vacuole in diploid but not haploid cells. This suggests a role of Hsv2 in protein sorting in diploid cells. The loop 6C/D of PROPPINs partially inserts into membranes causing their bending. We found that the membrane bending activity of Hsv2 is required for vacuole fragmentation and sorting in diploids but not for its autophagic function. Mutations in WDR45/WIPI4, the presumed mammalian homolog of Hsv2 cause the neurodegenerative disease BPAN, our study thus also helps to understand its underlying principles. CSC: cargo specific complex, FAS: fatty acid synthase, PAS: phagophore assembly site; PROPPIN: beta-propeller that binds phosphoinositides.
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PRKN-IMMT/MIC60 axis promotes myocardial ischemia-reperfusion injury via lysosomal degradation of GPX4.

Chen X, Liu S, Jiang M … +10 more , Wei M, Xu S, Lin JY, Huang ZB, Xie P, Cao J, Yang H, Bai Y, Lu G, Cui M

Autophagy · 2026 May · PMID 42132226 · Publisher ↗

Mitochondrial damage is a pivotal driver of myocardial ischemia-reperfusion (MIR) injury. While PRKN (parkin RBR E3 ubiquitin protein ligase), a key E3 ubiquitin ligase in the PINK1 (PTEN induced kinase 1)-PRKN mitophagy... Mitochondrial damage is a pivotal driver of myocardial ischemia-reperfusion (MIR) injury. While PRKN (parkin RBR E3 ubiquitin protein ligase), a key E3 ubiquitin ligase in the PINK1 (PTEN induced kinase 1)-PRKN mitophagy pathway, has been extensively studied, its role and mechanisms in acute MIR injury remain incompletely understood. Here, we demonstrated that PRKN exacerbates MIR injury by promoting cardiomyocyte ferroptosis under hypoxia-reoxygenation (H/R) conditions. Mechanistically, PRKN interacts with and mediates the ubiquitination and proteasomal degradation of IMMT/MIC60 (inner membrane mitochondrial protein), a core mitochondrial inner membrane protein essential for cristae architecture and mitochondrial integrity. This disruption of IMMT facilitates lysosomal degradation of GPX4 (glutathione peroxidase 4), a major ferroptosis suppressor, thereby triggering ferroptosis. Consistent with these findings, cardiac-specific knockout mice displayed increased susceptibility to MIR injury . Our findings establish PRKN-driven IMMT degradation as a key pathological mechanism in MIR injury and identify the PRKN-IMMT axis as a potential therapeutic target for cardioprotection.: ATG5, autophagy related 5; ATP, adenosine triphosphate; CCCP, carbonyl cyanide m-chlorophenylhydrazone; CHX, cycloheximide; cKO, cardiomyocyte-specific knockout; CQ, chloroquine; CRISPR, clustered regularly interspaced short palindromic repeats; EF, ejection fraction; Fer-1, ferrostatin-1; FS, fractional shortening; GO, Gene Ontology; GPX4, glutathione peroxidase 4; GST, glutathione S-transferase; gRNA, guide RNA; hiPSC-CMs, human induced pluripotent stem cell-derived cardiomyocytes; H/R, hypoxia-reoxygenation; IF, immunofluorescence; IHC, immunohistochemistry; IMMT/MIC60, inner membrane mitochondrial protein; IP, immunoprecipitation; LoxP, locus of X-overP1; KO, knockout; KR, lysine residues mutated to arginine; MDA, malondialdehyde; MFN2, mitofusin 2; MIR, myocardial ischemia reperfusion; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mtROS, mitochondrial reactive oxygen species; NAC, N-acetylcysteine; OMM, outer mitochondrial membrane; PRKN, parkin RBR E3 ubiquitin protein ligase; RAB7, RAB7, member RAS oncogene family; RNA-seq, RNA sequencing; UB, ubiquitin; WB, western blot; WT, wild-type.
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The N-degron pathway regulates glucose and insulin homeostasis through the lysosomal degradation of RXRA/RXRα via SQSTM1/p62.

Jung EJ, Kim HY, Bae TH … +13 more , Choi EN, Lim H, Kim M, Mun SR, Lee YJ, Hahn S, Lee DR, Park WJ, Suh YH, Kwon YT, Son YS, Kim HY, Park JW

Autophagy · 2026 May · PMID 42132221 · Publisher ↗

Central to the pathogenesis of type 2 diabetes (T2D) is the failure in insulin secretion from pancreatic β-cells associated with insulin resistance. The nuclear receptor RXRA/RXRα (retinoid X receptor alpha) is a transcr... Central to the pathogenesis of type 2 diabetes (T2D) is the failure in insulin secretion from pancreatic β-cells associated with insulin resistance. The nuclear receptor RXRA/RXRα (retinoid X receptor alpha) is a transcriptional regulator of insulin secretion and systemic glucose metabolism. Here, we show that the macroautophagic/autophagic receptor SQSTM1/p62 (sequestosome 1) sequesters RXRA for lysosomal degradation to modulate glucose metabolism and insulin secretion. Under glucolipotoxicity, RXRA is released from SQSTM1 to inhibit mitochondrial respiration and insulin secretion and to induce lipogenesis. SQSTM1-dependent degradation of RXRA was reconstituted and mice using ATB1002, a chemical N-degron designed to bind and activate SQSTM1 as an N-recognin of the N-degron pathway. In prediabetic and T2D models, SQSTM1 agonists induced the lysosomal degradation of RXRA, and enhanced glucose-stimulated insulin secretion and insulin responsiveness. These results identify SQSTM1 as a master regulator in glucose metabolism and insulin secretion, providing a therapeutic means to treat T2D.: ATLs: autophagy targeting ligands; AUC: area under the curve; ATP: adenosine triphosphate; co-IP: co-immunoprecipitation; GSIS: glucose-stimulated insulin secretion; GTT: glucose tolerance test; HFD: high-fat diet; i.p.: intraperitoneally; LBD: ligand binding domain; NR1H3/LXRα: nuclear receptor subfamily 1 group H member 3; Nt: N-terminal; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; RER: respiratory exchange ratio; RXRA/RXRα: retinoid X receptor alpha; SQSTM1/p62: sequestosome 1; T2D: type 2 diabetes; TG: triglycerides; TIW: three times per week; UBA: ubiquitin-associated domain; ZZ: zinc finger.
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Intracellular lipopolysaccharide binds RETREG1/FAM134B to regulate ER remodeling upon bacterial infection.

Cheng YL, Mello-Vieira J, Covarrubias-Pinto A … +15 more , Gonzalez A, Kumar Kuncha S, Kew C, Zhang K, Awais Afzal M, Diab N, Borchert S, Hong SY, Huang TC, Chen W, Mato UG, Hornef MW, Hübner CA, Hensel M, Dikic I

Autophagy · 2026 May · PMID 42117627 · Publisher ↗

Selective autophagy of the endoplasmic reticulum (ER), termed ERphagy or reticulophagy, plays a key role in organelle remodeling and cellular homeostasis. However, whether and how ERphagy is regulated during Gram-negativ... Selective autophagy of the endoplasmic reticulum (ER), termed ERphagy or reticulophagy, plays a key role in organelle remodeling and cellular homeostasis. However, whether and how ERphagy is regulated during Gram-negative bacteria infection to influence host responses remains unclear. Here, we show that serovar Typhimurium releases lipopolysaccharide (LPS) that colocalizes with RETREG1/FAM134B, a reticulon-like ER-resident receptor for ERphagy. Cytosolic delivery of LPS, either during infection or via transfection, markedly increases RETREG1- and LC3B-decorated ER fragments. Mechanistically, affinity-isolation assays demonstrate that LPS directly binds RETREG1 through interactions between lipid A and positively charged residues within its amphipathic helices and C-terminal region. This interaction promotes RETREG1 oligomerization and drives ER membrane fragmentation, a process further amplified by the O-antigen moiety of LPS. The resulting ER fragments accumulate around LC3-positive -containing vacuoles, facilitating bacterial clearance. Importantly, both intracellular and extracellular exploit outer membrane vesicles (OMVs) to deliver LPS into the host cytosol, triggering RETREG1 activation and ER remodeling. Collectively, our findings reveal a previously unrecognized host response by which LPS of Gram-negative bacteria are sensed by the host ERphagy machinery to promote xenophagy and enhance antibacterial defense.: AH: amphipathic helix; BMDMs: bone-marrow-derived macrophages; Co-IP: co-immunoprecipitation; BafA1: bafilomycin A; Cterm: C-terminal region (Cterm); CFU: colony-forming units; DAPI: 4',6-diamidino-2-phenylindole; ER: endoplasmic reticulum; EPEC: enteropathogenic ; GBP: guanylate binding protein; Gm12250/IRGB10: predicted gene 12250; KDO: keto-3-deoxy-octonate; LPR: lipid-to-protein ratio; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; mtLIR: LC3B-interacting region mutant; MDP: muramyl dipeptide; OMVs: outer membrane vesicles; O-Ag: O-antigen; OmpA: outer membrane protein A; RHD: reticulum homology domain; R-LPS: rough-LPS; S-LPS: smooth-LPS; SCVs: -containing vacuoles; SFB: S-protein-FLAG-streptavidin binding peptide; TM: transmembrane domain; TEM: transmission electron microscopy; WT: wild-type.
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A role for CASM in the repair of damaged Golgi architecture.

Oh S, Ullah S, Saha B … +1 more , Mandell MA

Autophagy · 2026 May · PMID 42115886 · Full text

The term CASM describes a process in which MAP1LC3B/LC3B and other Atg8-family proteins are covalently ligated to lipids in damaged endomembranes. While CASM is commonly described as a cytoprotective response to multiple... The term CASM describes a process in which MAP1LC3B/LC3B and other Atg8-family proteins are covalently ligated to lipids in damaged endomembranes. While CASM is commonly described as a cytoprotective response to multiple types of membrane damage, how CASM helps cells maintain homeostasis is still unclear. Here, we show that CASM maintains Golgi apparatus architecture following the loss of TRIM46, a ubiquitin ligase with roles in microtubule organization. TRIM46 deficient cells were notable for enhanced TFEB-driven lysosomal biogenesis and Golgi ribbon fragmentation, with colocalization of the -Golgi marker TGOLN2 and the Atg8-family proteins LC3B and GABARAP. Further studies revealed that the Golgi Atg8ylation seen in knockout cells was not degradative and mechanistically resembled CASM. Genetic inhibition of CASM in TRIM46 deficient cells reduced TFEB activation and exacerbated the Golgi morphology defects, suggesting that CASM contributes to Golgi repair. Accordingly, Golgi reformation after drug-induced fragmentation was impaired upon knockdown of CASM genes. Together, these studies identify lysosomal biogenesis and CASM as coordinated features of a Golgi damage response, with CASM acting to preserve Golgi integrity. AMPK (AMP-activated protein kinase); ATG3 (autophagy related 3); ATG5 (autophagy related 5); ATG7 (autophagy related 7); ATG12 (autophagy related 12); ATG13 (autophagy related 13); ATG16L1 (autophagy related 16 like 1); BECN1 (beclin 1); CASM, conjugation of Atg8 to single membranes; GABARAP (GABA type A receptor-associated protein); GABARAPL1 (GABA type A receptor associated protein like 1); GABARAPL2 (GABA type A receptor associated protein like 2); GOLGA2 (golgin A2); HT (HaloTag); HL (HaloTag ligand); MAP1LC3A/LC3A (microtubule associated protein 1 light chain 3 alpha); MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta); MAP1LC3C/LC3C (microtubule associated protein 1 light chain 3 gamma); MTORC1 (mechanistic target of rapamycin kinase complex 1); PE (phosphatidylethanolamine); PIK3C3/VPS34 (phosphatidylinositol 3-kinase catalytic subunit type 3); PS (phosphatidylserine); TECPR1 (tectonin beta-propellor repeat containing 1); SQSTM1/p62 (sequestosome 1); TFEB (transcription factor EB); TFE3 (transcription factor binding to IGHM enhancer 3); TGOLN2 (trans-golgi network protein 2); TRIM46 (tripartite motif containing 46); ULK1 (unc-51 like autophagy activating kinase 1); ULK2 (unc-51 like autophagy activating kinase 2): VAIL (V-ATPase-ATG16L1 induced LC3 lipidation).
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