Autophagy [JOURNAL]
Sun
200 papers
CAMKV is an ISG and facilitates the degradation of rabies virus phosphoprotein via SQSTM1-mediated selective autophagy.
Wang J, Huo H, Tao Y … +7 more , Wang J, Wang X, Wen Z, Ge J, Chen W, Bu Z, Shuai L
Autophagy · 2026 Jul · PMID 42402699 · Publisher ↗
Once rabies virus (RABV) gains access to the central nervous system, infection almost inevitably results in fatal outcomes, and our incomplete understanding of viral pathogenesis remains a major barrier to effective ther...
Once rabies virus (RABV) gains access to the central nervous system, infection almost inevitably results in fatal outcomes, and our incomplete understanding of viral pathogenesis remains a major barrier to effective therapeutic intervention. Here, we identify as an interferon-stimulated gene (ISG) that drives the macroautophagic/autophagic degradation of RABV phosphoprotein (P), thereby potently suppressing viral replication . Notably, overexpression of CAMKV significantly delays disease progression in mice challenged with a street strain of RABV. Mechanistically, CAMKV interacts with both RABV P and SQSTM1, promoting SQSTM1-mediated selective autophagic clearance of P and thereby restricting RABV transcription and replication. Collectively, our findings establish CAMKV as a critical host antiviral effector that functions through selective autophagy, highlighting CAMKV as a promising molecular target for the development of novel therapeutics against lethal RABV infection. Abbreviation: 3-MA: 3-methyladenine; ABLV: Australian bat lyssavirus; ATG: autophagy related; AKT: AKT serine/threonine kinase; Baf-A1: bafilomycin A1; CAMKV: CaM kinase like vesicle associated; CAMK2: calcium/calmodulin dependent protein kinase II; co-IP: co-immunoprecipitation; CQ: chloroquine; DUVV: Duvenhage virus; DMSO: dimethyl sulfoxide; EBLV-1: European bat lyssavirus 1; ISG: interferon stimulated gene; LAMP1: lysosome associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mdivi-1: mitochondrial division inhibitor-1; MLD₅₀: 50% mouse lethal dose; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; qPCR: quantitative real-time polymerase chain reaction; RABV: rabies virus; SQSTM1/p62: sequestosome 1; WT: wild type.
Tegument protein UL16 of herpes simplex virus 1 suppresses the innate immune response by downregulating MAVS abundance via mitophagy.
Wang J, Zhu R, Yi P … +2 more , Gan M, Long F
Autophagy · 2026 Jul · PMID 42391028 · Publisher ↗
Herpes simplex virus 1 (HSV-1) is a globally prevalent pathogen that poses a significant health threat due to its lifelong latency. This persistence is driven by intricate immune evasion mechanisms, the deciphering of wh...
Herpes simplex virus 1 (HSV-1) is a globally prevalent pathogen that poses a significant health threat due to its lifelong latency. This persistence is driven by intricate immune evasion mechanisms, the deciphering of which remains a challenge. Here, we identified the HSV-1 tegument protein UL16 as a novel viral immunosuppressive factor, which significantly suppresses the RIGI-like receptor (RLR)-mediated antiviral immunity. We found that UL16 can interact with MAVS (mitochondrial antiviral signaling protein) and induce its degradation, thereby inhibiting type I interferon (IFN-I) production. Further investigation revealed that UL16-induced MAVS degradation was facilitated via mitophagy involving the mitochondrial cargo receptor FUNDC1 (FUN14 domain containing 1). Knockout of expression completely disrupted UL16-induced MAVS degradation and restricted HSV-1 replication. In contrast, overexpression of FUNDC1 augmented the suppressive effect of UL16 on MAVS-triggered IFN-I signaling and consequently benefited viral replication. Notably, the C-terminal domain (CTD) of UL16 primarily accounted for its immunosuppressive function, which was also demonstrated to be essential for UL16 engagement with MAVS, FUNDC1 and MAP1LC3/LC3 (microtubule associated protein 1 light chain 3). A conserved LC3-interacting region (LIR) motif within the UL16 CTD was identified to play a critical role in LC3 recruitment enhancement. Furthermore, the UL16-deficient HSV-1 exhibited markedly attenuated viral infectivity and pathogenicity . In summary, our findings uncover a previously uncharacterized pathway through which HSV-1 UL16 subverts host immunity by inducing mitophagy. This study provides critical insights into host-pathogen interactions and establishes a rational foundation for developing novel therapeutics against HSV-1 infection.:3-MA: 3-methyladenine; BNIP3L/NIX: BCL2 interacting protein 3 like; BSA: bovine serum albumin; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CARD: caspase recruitment domain; Cas9: CRISPR-associated system 9; CGAS: cyclic GMP-AMP synthase; co-IP: co-immunoprecipitation; COX8: cytochrome c oxidase subunit 8; CQ: chloroquine; CRISPR: clustered regulatory interspaced short palindromic repeat; CTD: C-terminal domain; Ctrl: control; CXCL10: C-X-C motif chemokine ligand 10; DAPI: 4,'6-diamidino-2-phenylindole; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; ds: double-stranded; FBS: fetal bovine serum; FUNDC1: FUN14 domain containing 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HEK: human embryonic kidney; HSV-1: herpes simplex virus 1; IAV: influenza A virus; IFIH1/MDA5: interferon induced with helicase C domain 1; IFIT1/ISG56: interferon induced protein with tetratricopeptide repeats 1; IFN-I: type I interferon; IgG: Immunoglobulin G; IRF3: interferon regulatory factor 3; ISGs: IFN-stimulated genes; kDa: kilodalton; KO: knockout; KSHV: Kaposi sarcoma-associated herpesvirus; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MG132: cbz-leu-leu-leucinal; MOI: multiplicity of infection; NanoBiT: NanoLuc Binary Technology; NC: negative control; NTD: N-terminal domain; OPTN: optineurin; p-: phosphorylated; PFU: plaque-forming unit; PINK1: PTEN induced kinase 1; poly(I:C): polyinosinic-polycytidylic acid; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; qPCR: quantitative polymerase chain reaction; RIGI/RIG-I: RNA sensor RIG-I; RLR: RIGI-like receptor; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SeV: Sendai virus; sgRNA: single guide RNA; shRNA: short hairpin RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TM: transmembrane; TOMM20: translocase of outer mitochondrial membrane 20; TRAF: TNF receptor associated factor; TUFM: Tu translation elongation factor, mitochondrial; UL16: unique long region 16; VSV: vesicular stomatitis virus; VZV: varicella zoster virus; WCL: whole-cell lysate; WT: wild-type; Z-VAD-FMK: carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone.
AARS2-mediated lactylation of ULK1 promotes autophagy-dependent progression of clear cell renal cell carcinoma.
Zeng X, Zhu Y, Xiao Y … +12 more , Zhang Z, Chen X, Wei D, Huang C, Liu K, Shi X, Luo F, Wang Q, Lin Z, Xu W, Tan W, Zheng Z
Autophagy · 2026 Jul · PMID 42381569 · Publisher ↗
Macroautophagy/autophagy is an evolutionarily conserved degradation pathway wherein cytoplasmic components are sequestered within double-membrane autophagosomes for lysosomal delivery. The initiation of autophagy is gove...
Macroautophagy/autophagy is an evolutionarily conserved degradation pathway wherein cytoplasmic components are sequestered within double-membrane autophagosomes for lysosomal delivery. The initiation of autophagy is governed by autophagy-related (ATG) proteins, with the ULK1 kinase complex serving as the most upstream regulator. However, how ULK1 senses and integrates metabolic signals via post-translational modifications remains poorly understood. Here, we discover that ULK1 undergoes lactylation at lysine 46, catalyzed by the mitochondrial aminoacyl-tRNA synthetase AARS2, in response to autophagic stimuli. This modification promotes ULK1 kinase activity, leading to enhanced and selective phosphorylation of its downstream substrate ATG14 at Ser29, thereby activating the class III PtdIns3K complex and facilitating autophagosome biogenesis. Furthermore, we demonstrate that AARS2-mediated ULK1 lactylation drives autophagic flux and promotes tumor metastasis in clear cell renal cell carcinoma (ccRCC), and that a cell-penetrating peptide targeting K46 lactylation suppresses ccRCC progression and . Our study identifies lactylation as a novel regulatory mechanism controlling autophagy initiation and suggests that targeting AARS2-mediated ULK1 lactylation could be a potential strategy for treating ccRCC.
Mechanistic studies of autophagic cargo recruitment and membrane shaping through in vitro reconstitution.
Zhang W, Litschel T, Schreiber A … +2 more , D'Antuono R, Tooze SA
Autophagy · 2026 Jun · PMID 42377218 · Publisher ↗
Macroautophagy/autophagy, a conserved intracellular catabolic pathway, removes deleterious cytosolic material to maintain homeostasis and survival. Upon autophagy induction, a unique double-membraned structure, the phago...
Macroautophagy/autophagy, a conserved intracellular catabolic pathway, removes deleterious cytosolic material to maintain homeostasis and survival. Upon autophagy induction, a unique double-membraned structure, the phagophore, forms and engulfs cytosolic material, the cargo, as it closes to become an autophagosome. Mammalian Atg8-family proteins (ATG8s) are ubiquitin-like proteins which are essential for engulfment of the cargo and membrane closure. ATG8s are recruited to the phagophore by ATG12-ATG5-ATG16L1, an E3-like ligase which is recruited by PtdIns3P-binding WIPI proteins. Covalent lipidation of the ATG8s to phosphatidylethanolamine by the E3 ligase occurs specifically on the phagophore membrane allowing recruitment of cytosolic cargo and cargo receptors, such as SQSTM1/p62. While ATG8-cargo receptor interactions are well established, how the ATG8s bind cargo and cargo receptors on the inner membrane of the phagophore has not been studied. To recapitulate these events, we use giant unilamellar vesicles (GUVs) and encapsulate protein machinery and cargo, generating a membrane platform to which ATG8 proteins can be recruited. Inside the GUVs we reconstituted WIPI2B-directed and cargo-directed ATG8 lipidation revealing distinct roles of WIPI2B and SQSTM1 in initiating ATG8 conjugation. We show that SQSTM1 and SQSTM1 droplets are recruited to the GUV inner membrane through interaction with membrane bound ATG8s. Through the development of a bead-based membrane deformation assay, we show redistribution and local enrichment of membrane-bound ATG8s occurs upon binding to SQSTM1 droplets. Our work demonstrates fundamental molecular mechanisms into phagophore-ATG8-cargo interactions providing novel model systems to investigate ATG8-cargo interactions on the inner phagophore membrane.:ATG: autophagy related; cDICE: continuous droplet interface crossing encapsulation; DOPE: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; GABARAP: GABA type A receptor-associated protein; GUV: giant unilamellar vesicle; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LIR: LC3-interacting region; LUV: large unilamellar vesicle; NBD: 7-nitrobenz-2-oxa-1,3-diazol-4-yl; PE: phosphatidylethanolamine; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; PolyUb: K63-linked polyubiquitin; POPC: 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine; POPE: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine; Rh-PE: 18:1 Liss Rhod PE; SQSTM1/p62: sequestosome 1; WIPI2B: WD repeat domain, phosphoinositide interacting 2B.
Receptor-cargo coupling during ER-autophagy depends on coat proteins and ER membrane properties.
Chen S, Banerjee S, Novick P … +2 more , Prinz WA, Ferro-Novick S
Autophagy · 2026 Jul · PMID 42372124 · Publisher ↗
Selective autophagy of the endoplasmic reticulum (reticulophagy) is driven by receptor-mediated ER remodeling. Reticulophagy receptors are essential for ER turnover. Productive cargo recognition during autophagosome-medi...
Selective autophagy of the endoplasmic reticulum (reticulophagy) is driven by receptor-mediated ER remodeling. Reticulophagy receptors are essential for ER turnover. Productive cargo recognition during autophagosome-mediated reticulophagy depends on the interaction of the receptor with the COPII subunit Sfb3/Lst1 (SEC24C in mammals) as well as the phospholipid composition of the ER. We unexpectedly found that the conserved reticulophagy receptor Atg40 traffics to the vacuole/lysosome without cargo (ER membrane proteins) or Sfb3/Lst1 in neutral lipid-deficient mutant cells. Comprehensive lipidomic profiling of this lipid mutant revealed a shift in the phosphatidylethanolamine (PE)-to-phosphatidylcholine (PC) ratio, a compositional change predicted to alter biophysical properties of the ER, including membrane bendability. The discovery that membrane properties regulate receptor - cargo coupling efficiency at autophagic sites, as they do at secretory exit sites, extends current mechanistic models of reticulophagy and suggests membrane properties may also affect cargo selection on other types of selective autophagy pathways.
Translation control of autophagy genes modulates cellular response to hydroxyurea-induced genotoxic stress.
Mohanan G, Nag K, Senger HS … +2 more , J P, Rajyaguru PI
Autophagy · 2026 Jun · PMID 42371698 · Publisher ↗
The fine balance between cellular homeostasis and stress response is crucial for cell survival under conditions of genotoxic stress. Here, we identify a regulatory role for the translation repressor Sbp1 in modulating au...
The fine balance between cellular homeostasis and stress response is crucial for cell survival under conditions of genotoxic stress. Here, we identify a regulatory role for the translation repressor Sbp1 in modulating autophagy during hydroxyurea (HU)-induced replication stress. We observe that Sbp1 localizes to reversible, mRNA-containing cytoplasmic granules specifically upon HU treatment in an RGG motif-dependent manner. Loss of Sbp1 leads to selective translational upregulation of key autophagy genes , , and . Consistent with these translational changes, cells exhibit increased selective macroautophagy/autophagy and enhanced bulk autophagy, whereas Sbp1 overexpression suppresses both processes. Interestingly, overexpression of Sbp1 shifts DNA repair toward non-homologous end joining (NHEJ) repair, linking altered autophagy to genome maintenance. Together, these findings identify Sbp1 as a negative regulator of autophagy during replication stress and suggest a regulatory axis linking granule-mediated mRNA sequestration, translational control of autophagy factors, and the cellular response to genotoxic stress.: CHX: cycloheximide; CPT: camptothecin; DDR: DNA damage response; GTA: genotoxin-associated targeted autophagy; HR: homologous recombination; HU: hydroxyurea; MMS: methyl methanesulfonate; mRNPs: mRNA-protein complexes; NHEJ: non-homologous end joining; P-bodies: processing bodies; RBPs: RNA binding proteins.
RAPSN/rapsyn aggregation-induced HSPA/HSP70-BAG3 aggrephagy maintains CHRN integrity in myasthenia gravis.
Liu Y, Xia G, Shi H … +6 more , Zhu S, Li H, Shi Y, Ouyang W, Xu C, Du A
Autophagy · 2026 Jun · PMID 42366592 · Publisher ↗
Accelerated CHRN/AChR/nicotinic acetylcholine receptor internalization induced by auto-antibodies impairs neuromuscular junction transmission and contributes to myasthenia gravis (MG), a typical autoimmune disease. Altho...
Accelerated CHRN/AChR/nicotinic acetylcholine receptor internalization induced by auto-antibodies impairs neuromuscular junction transmission and contributes to myasthenia gravis (MG), a typical autoimmune disease. Although CHRN internalization is well established in MG pathogenesis, the downstream cellular events, especially those related to autophagy, remain poorly described. Here, we report that RAPSN/rapsyn, an intracellular CHRN-binding protein essential for its clustering, accumulates as aggregates in experimental autoimmune myasthenia gravis (EAMG) mice. In CHRN antibody-treated myotubes, RAPSN dissociates from internalized CHRN and forms aggregates due to exposure of its hydrophobic domains. These aggregates in turn impair the trafficking and membrane incorporation of newly synthesized CHRN, thereby exacerbating CHRN loss. Notably, the accumulation of RAPSN aggregates facilitates formation of HSPA/HSP70-BAG3 complex, which recognizes and transports the aggregates along microtubules to form perinuclear aggresomes for subsequent lysosomal degradation. Accordingly, pharmacological inhibition or knockdown of HSPA-BAG3 complex increases RAPSN aggregation, which participates in enhanced CHRN loss and worsened muscle weakness in EAMG mice. This study identifies HSPA-BAG3 aggrephagy as a protective mechanism that clears RAPSN aggregates to maintain CHRN integrity and suggests a potential therapeutic strategy for MG. 3-MA: 3-methyladenine; AAV: adeno-associated virus; CASA: chaperone-assisted selective autophagy; CHRN/nicotinic acetylcholine receptor: cholinergic receptor nicotinic; CHRN-ab: CHRN antibodies; CHX: cycloheximide; CMAP: compound muscle action potential; CQ: chloroquine; EAMG: experimental autoimmune myasthenia gravis; ER: endoplasmic reticulum; GAS: gastrocnemius; MAP1LC3A/B: microtubule associated protein 1 light chain 3 alpha/beta; MG: myasthenia gravis; NMJ: neuromuscular junction; Rapa: rapamycin; RAPSN/rapsyn: receptor associated protein of the synapse; SQSTM1: sequestosome 1; TA: tibialis anterior; αBTX-A594: α-bungarotoxin-Alexa-594.
TMEM184A-mediated autophagy in MHC-I degradation promotes tumor immune evasion.
Li W, Li K, Shi Z … +13 more , Chen Y, Cheng M, Zhao B, Wang S, Diao S, Ye S, Wang X, Li J, Zhang Z, Qiao Y, Xiong W, Wang W, Ma W
Autophagy · 2026 Jun · PMID 42345610 · Publisher ↗
The dominance of immunotherapy-insensitive MSS colorectal cancers (CRCs), which represent most cases, contrasts sharply with the treatable MSI-H minority, making this disparity a key obstacle to progress. It is urgent to...
The dominance of immunotherapy-insensitive MSS colorectal cancers (CRCs), which represent most cases, contrasts sharply with the treatable MSI-H minority, making this disparity a key obstacle to progress. It is urgent to identify genes driving immune evasion in MSS CRCs. Here, using a genome-wide CRISPR screen in a syngeneic tumor model under immune pressure, we identify TMEM184A as a previously unknown tumor-intrinsic regulator of immune evasion. Its genetic deletion in murine models enhanced CD8 T cell infiltration and increased surface MHC-I expression on cancer cells, as shown by flow cytometry, immunohistochemistry, immunofluorescence and RNA-seq. Mechanistically, TMEM184A functions as a novel macroautophagy/autophagy receptor by binding GABARAPL2, directly promoting the autophagic degradation of IFNG-induced MHC-I. In murine models, genetic deletion of led to a significant increase in both CD8 T cell infiltration and surface MHC-I expression on cancer cells. Functional studies in vivo and in vitro confirmed that this impaired antigen presentation causally facilitates immune evasion. Our findings establish MHC-I autophagic degradation as a critical pathway regulating immune evasion and position TMEM184A as a pivotal molecular hub in this process. Notably, treatment with the autophagy inhibitor chloroquine significantly increased surface MHC-I levels and enhanced the efficacy of anti-PDCD1/PD-1 therapy specifically in TMEM184A-high tumors. This work suggests that targeting TMEM184A or its associated autophagic pathway could restore antigen presentation in MHC-I-deficient tumors, offering a potential combinatorial strategy to overcome adaptive immune resistance in multiple malignancies.: AKP organoids:andknockout, KRASmutation organoids; CRC: colorectal cancer; CQ: chloroquine; GABARAPL2/Atg8: GABA type A receptor associated protein like 2; IF: immunofluorescence; IFNG: interferon gamma; IHC: immunohistochemistry; MHC-I: major histocompatibility complex I; qRT-PCR: quantitative reverse transcription PCR; MSI-H: microsatellite instability-high; MSS: microsatellite-stable; TMEM184A: transmembrane proteins 184a.
Robust and sensitive ELISA detection of total and activated PRKN.
Watzlawik JO, Bustillos BA, Rodriguez Martinez C … +5 more , Dickson DW, Wszolek ZK, Ross OA, Springer W, Fiesel FC
Autophagy · 2026 Jul · PMID 42343639 · Publisher ↗
Parkinson disease (PD) is closely linked to disruptions in mitochondrial quality control, a process regulated by the ubiquitin kinase PINK1 and the E3 ubiquitin ligase PRKN/parkin. Upon mitochondrial damage, PINK1 phosph...
Parkinson disease (PD) is closely linked to disruptions in mitochondrial quality control, a process regulated by the ubiquitin kinase PINK1 and the E3 ubiquitin ligase PRKN/parkin. Upon mitochondrial damage, PINK1 phosphorylates ubiquitin, which in turn recruits and activates PRKN. Full activation of PRKN is mediated by PINK1-dependent phosphorylation of PRKN at serine 65, which leads to widespread ubiquitination of mitochondrial substrates and amplifies the mitophagy response. Disruption of this pathway results in mitochondrial accumulation, oxidative stress, and neuronal death, all key mechanisms of PD pathogenesis. Genetic studies have shown biallelic loss-of-function mutations in PRKN are the most common cause of early-onset PD. Although the role of haploinsufficiency remains under investigation, PRKN protein becomes insoluble and inactive with aging or post-translational modifications, indicating that functional protein levels are a key determinant of disease risk. Reliable quantification of total and activated PRKN in samples has not been feasible, limiting research and clinical assessment. To address this, we developed and validated knockout (KO)-verified sandwich ELISA assays that quantify both total PRKN and PINK1-phosphorylated p-S65-PRKN. These assays provide absolute quantification of PRKN, improving functional diagnosis, and patient stratification in PD. Application of these methods established the concentration of PRKN in cells and in brain and revealed significant effects of a common genetic PRKN variant, further highlighting the importance of determining functional PRKN protein levels. The developed immunoassays complement previously established PINK1 and p-S65-Ub measurements, enhancing mechanistic insight into mitophagy and enabling effective monitoring of PD therapies and other neurodegenerative diseases. AD: Alzheimer disease; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECL: electrochemiluminescence; ELISA: enzyme-linked immunosorbent assay; IBR: In-between-RING; iPSC: induced pluripotent stem cell; KO: knockout; LoB: limit of blank; LoD: limit of detection; LoQ: limit of quantification; MSD: Meso Scale Discovery; PD: Parkinson disease; p-S65-PRKN: serine 65 phosphorylated PRKN; p-S65-Ub: serine 65 phosphorylated ubiquitin; REP: repressor element of PRKN; RING: really interesting new gene; Ub: ubiquitin; UBL: ubiquitin-like domain; VCL: vinculin; WT: wild-type.
Foot-and-mouth disease virus regulates glycolysis through autophagy to drive viral replication in vivo and in vitro.
Xue Q, Liu H, Dong Z … +5 more , Zhu Y, Yang F, Cao W, Zhu Z, Zheng H
Autophagy · 2026 Jul · PMID 42338171 · Publisher ↗
Viruses, lacking an intrinsic metabolic network, exploit host cell metabolism in order to hijack resources for their own replication. However, the regulatory relationship between foot-and-mouth disease virus (FMDV) and e...
Viruses, lacking an intrinsic metabolic network, exploit host cell metabolism in order to hijack resources for their own replication. However, the regulatory relationship between foot-and-mouth disease virus (FMDV) and energy metabolism remains incompletely elucidated. Here, metabolomic analysis was performed on PK-15 cells and tonsils infected with FMDV. Metabolites involved in glycolysis were significantly upregulated, whereas metabolites associated with the tricarboxylic acid (TCA) cycle were markedly downregulated and , which indicated that FMDV induced reprogramming of host cell energy metabolism, shifting it from oxidative phosphorylation (OXPHOS) to glycolysis. Furthermore, FMDV infection promoted glucose uptake and its subsequent utilization in FMDV-infected PK-15 cells, facilitating viral replication. Mechanistically, on the one hand, FMDV infection activated the AKT-MTOR-dependent macroautophagy/autophagy pathway to suppress the expression of OTUD4 (OTU deubiquitinase 4), upregulating HK2 (hexokinase 2) to facilitate glycolysis. On the other hand, FMDV infection decreased the level of mitochondrial SIRT3 (sirtuin 3) through PINK1-PRKN-dependent mitophagy, leading to the increase of HIF1A (hypoxia inducible factor 1 subunit alpha), HK2, phosphofructokinase 1 (PFK1), and PKM/PKM2 (pyruvate kinases M1/2), promoting glycolysis. Overall, this study elucidates how FMDV modulates glycolysis through two different autophagic pathways, which would contribute to our understanding of how the autophagy-glycolysis axis regulates viral replication, providing new avenues for developing antiviral strategies targeting metabolism.: 3-MA: 3-methyladenine; ACTB: actin beta; ATG: autophagy related; CQ: chloroquine; dpi: days post-infection; EV71: enterovirus 71; FMDV: foot-and-mouth disease virus; HK2: hexokinase 2; HIF1A: hypoxia inducible factor 1 subunit alpha; hpt: hours post-transfection; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; OTUD4: OTU deubiquitinase 4; OXPHOS: oxidative phosphorylation; PFK1: phosphofructokinase 1; PFKFB3: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; PKM/PKM2: pyruvate kinase M1/2; SIRT3: sirtuin 3; siRNA: small interfering RNA; TCID: 50% tissue culture infectious doses; TCA: tricarboxylic acid; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; WT: wild type.
Genome-wide CRISPR screen identifies as a key regulator of host autophagy and lipid metabolism important for proliferation.
Xu H, Liu H, Lu T … +10 more , Chen Y, Li Y, Zhu Y, Wei L, Fan B, Zhang Y, Zhang C, Fang R, Xie S, Shen B
Autophagy · 2026 Jul · PMID 42329082 · Publisher ↗
is a globally prevalent foodborne zoonotic pathogen that threatens animal production and human health. Consumption of undercooked meat like pork and lamb is a major route of human infection. In this study, we performed a...
is a globally prevalent foodborne zoonotic pathogen that threatens animal production and human health. Consumption of undercooked meat like pork and lamb is a major route of human infection. In this study, we performed a genome-wide CRISPR knockout screen in the porcine cell line PK15 to identify host factors that are critical for replication. The results showed that disrupting the (extracellular leucine rich repeat and fibronectin type III domain containing 2) gene in PK15 did not affect host cell growth, but significantly reduced the proliferation of parasites. Loss of decreased macroautophagy/autophagy in PK15 cells and impaired lipid metabolism, resulting in reduced lipid availability for the parasites and consequent suppression of proliferation. Exogenous lipid supplementation or pharmacological activation of autophagy could fully restore the replication of parasites in Δ cells. The requirement of host for optimal parasite proliferation was validated by constructing mice, which showed increased resistance to infection and reduced parasite burden, highlighting the value of in breeding -resistant animals. Notably, naturally occurring loss-of-function mutations in could be found in certain pig breeds, further indicating the feasibility of breeding -resistant animals like pigs, to reduce the transmission of . 3-MA: 3-methyladenine; ATG5: autophagy related 5; ATG7: autophagy related 7; BODIPY-C12: BODIPY FL C; CCK-8: Cell Counting Kit-8; ComN2: complemented with an ectopic copy of; ELFN2: extracellular leucine rich repeat and fibronectin type III domain containing 2;:homozygous knockout; FASII: type II synthesis pathway; GFP: green fluorescent protein; KO: knockout; LD: lipid droplets; MG: monoacylglycerol; MOI: multiplicity of infection; MTORC1: mechanistic target of rapamycin kinase complex 1; PV: parasitophorous vacuole; PVM: parasitophorous vacuole membrane; ; WT: wild type.
Efficient pharmacological modulation of autophagy in isolated muscle fibers: impact on excitation-contraction coupling.
Gaillard J, Malleval C, Dauvois C … +7 more , Gueloua L, Schreiber J, Kretz-Remy C, Gangloff YG, Allard B, Berthier C, Jacquemond V
Autophagy · 2026 Jun · PMID 42329081 · Publisher ↗
Macroautophagy/autophagy is a key regulator of muscle mass and of muscle adaptation to stress and defective autophagy is a feature of many muscle disorders. Still, how changes in autophagic flux influence the integrity a...
Macroautophagy/autophagy is a key regulator of muscle mass and of muscle adaptation to stress and defective autophagy is a feature of many muscle disorders. Still, how changes in autophagic flux influence the integrity and function of differentiated muscle fibers remains under-documented. Specifically, links between autophagy and mechanisms involved in Ca homeostasis and excitation-contraction coupling are largely unexplored. We developed an assay to monitor autophagy modulation in mouse muscle fibers maintained in culture. Exposure to 3-methyladenine, an inhibitor of autophagy initiation, reduced the density of autophagic vesicles. Conversely, hydroxychloroquine, a blocker of autolysosome formation, as well as two MTOR inhibitors that activate autophagy, rapamycin and torin-1, enhanced the vesicle density. The density of lysosomal vesicles was increased by MTOR inhibitors and by hydroxychloroquine, but insensitive to 3-methyladenine. Measurements of Ca signals associated with contractile activation revealed that voltage-activated sarcoplasmic reticulum Ca release was unaffected by torin-1 but was depressed in 3-methyladenine- and in hydroxychloroquine-exposed fibers, suggesting that restraining autophagic flux is detrimental to excitation contraction coupling. The density of the inner plasma membrane network that carries the electrical excitation was depressed by 3-methyladenine and hydroxychloroquine, likely contributing to the function defect. Results establish that autophagic flux is preserved and can be manipulated in cultured muscle fibers, and revealed the power of the approach to tackle the cellular and subcellular consequences of autophagy modulation. They also uncover the possibility that autophagy is a determinant of maintenance and/or function of excitation-contraction coupling, with a potential role in several muscle disease situations.: 3-MA: 3-methyladenine; EC: excitation-contraction; HCQ: hydroxychloroquine; MTM1: myotubularin 1; RYR1: ryanodine receptor 1.
Emodin induces defensive autophagy against white spot syndrome virus infection via targeting the hemocyanin-mediated endoplasmic reticulum-mitochondrial crosstalk in shrimp.
Zhang X, Shan LP, Liu L … +1 more , Chen J
Autophagy · 2026 Jul · PMID 42329080 · Publisher ↗
White spot syndrome virus (WSSV) devastates shrimp aquaculture, yet safe antivirals remain scarce. Here we identify a druggable host-directed pathway centered on hemocyanin (HMC). This pathway coordinates endoplasmic ret...
White spot syndrome virus (WSSV) devastates shrimp aquaculture, yet safe antivirals remain scarce. Here we identify a druggable host-directed pathway centered on hemocyanin (HMC). This pathway coordinates endoplasmic reticulum (ER)-mitochondrial crosstalk to promote WSSV replication, which could be counteracted by the natural anthraquinone emodin. In , emodin suppressed viral replication with a half maximal inhibitory concentration (IC) of 1.174 μM, improved survival in both therapeutic and prophylactic regimens, remained effective after per os administration, and retained antiviral activity in water for up to 4 d. Target fishing, orthogonal biophysics, and docking analyses show that emodin binds HMC (K = 4.49 μM) and interferes with HMC-HSPA5/BiP (heat shock protein family A (Hsp70) member 5) association. Mechanistically, emodin weakens the ITPR/IPR (inositol 1,4,5-trisphosphate receptor)-VDAC (voltage dependent anion channel)-MCU (mitochondrial calcium uniporter) conduit at ER-mitochondrial contact sites, thereby limiting Ca transfer, restoring mitochondrial membrane potential and organelle spacing, and attenuating ER stress. Untargeted metabolomics revealed that WSSV induced phosphoinositide and amino acid dysregulation, whereas emodin selectively normalizes phosphatidylinositol (PtdIns) and phosphatidylinositol 1,4,5-trisphosphate (PtdIns[1,4,5]P) signaling and rebalances amino acid, tricarboxylic acid (TCA) intermediates. Correspondingly, emodin inhibited phosphoinositide 3-kinase (PI3K)-AKT/protein kinase B-MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) signaling and restored lysosome-dependent macroautophagy/autophagy. RNAi or ITPR and MCU inhibition phenocopied emodin, whereas exogenous HMC or ER stress activation exacerbated infection and was mitigated by emodin or MCU blockade. These findings establish HMC-anchored ER-mitochondrial contact as a central proviral vulnerability and position emodin as a practical scaffold for next-generation antivirals in aquaculture. 2-APB: 2-aminoethyl diphenylborinate; 3-MA: 3-methyladenine; ΔΨm: mitochondrial membrane potential; AKT/protein kinase B: AKT serine/threonine kinase; ATG1/ULK1: autophagy related 1; ATG13: autophagy related 13; BSA: bovine serum albumin; CETSA: cellular thermal shift assay; Co-IP: co-immunoprecipitation; DAPI: 4',6-diamidino-2-phenylindole; DDIT3/Chop: DNA damage inducible transcript 3; DMSO: dimethyl sulfoxide; EAS6B: epoxy-activated sepharose 6B; EGTA: ethylene glycol tetraacetic acid; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EPC: epithelioma papulosum cyprini; ER: endoplasmic reticulum; HMC: hemocyanin; HPLC-MS: high performance liquid chromatography-mass spectrometry; HRP: horseradish peroxidase; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; HSPA9/GRP75: heat shock protein family A (Hsp70) member 5; ITPR/IPR: inositol 1,4,5-trisphosphate receptor; KEGG: Kyoto Encyclopedia of Genes and Genomes; LAMP1: lysosome associated membrane protein 1; LC-MS: liquid chromatography-mass spectrometry; MAMs: mitochondria-associated ER membranes; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCU: mitochondrial calcium uniporter; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OPLS-DA: orthogonal partial least squares-discriminant analysis; PA: phosphatidic acid; PBS: phosphate-buffered saline; PC: phosphatidylcholine; PCA: principal component analysis; PE: phosphatidylethanolamine; PI3K: phosphoinositide 3-kinase; PLS-DA: partial least squares-discriminant analysis; PS: phosphatidylserine; PtdIns: phosphatidylinositol; PtdIns(1,4,5)P: phosphatidylinositol (1,4,5)-trisphosphate; PtdIns(3,4,5)P: phosphatidylinositol (3,4,5)-trisphosphate; PtdIns(4,5)P: phosphatidylinositol (4,5)-bisphosphate; RPS6KB1/S6K1: ribosomal protein S6 kinase B1; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SQSTM1/p62: sequestosome 1; TCA: tricarboxylic acid cycle; TEM: transmission electron microscopy; TFEB: transcription factor EB; UPR: unfolded protein response; VDAC: voltage dependent anion channel; WSSV: white spot syndrome virus; XBP1: X-box binding protein 1.
Oxidative stress-preconditioned exosomes target BMF to restore mitophagy for alleviating intervertebral disc degeneration.
Teng Y, Wu T, Wu Y … +10 more , Ge J, Chen R, Sun X, Zhao L, Zhong X, Yan Q, Zhang Q, Yang H, Niu J, Zou J
Autophagy · 2026 Jun · PMID 42329074 · Publisher ↗
Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) represent a promising cell-free strategy for intervertebral disc degeneration (IDD). Here, we obtained oxidative stress-preconditioned exosomes (O-Exos) fr...
Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) represent a promising cell-free strategy for intervertebral disc degeneration (IDD). Here, we obtained oxidative stress-preconditioned exosomes (O-Exos) from BMSCs exposed to low-concentration hydrogen peroxide. Compared with exosomes from untreated cells (N-Exos), O-Exos more effectively delayed nucleus pulposus (NP) cell senescence and attenuated IDD and . The superior effects of O-Exos were associated with restoration of mitophagy and improved mitochondrial homeostasis in TNF/TNF-α-treated NP cells. BMF (Bcl2 modifying factor) was identified as a functionally relevant downstream target suppressed by O-Exos, and deficiency promoted mitophagy and alleviated IDD. Further analyses showed that O-Exos relieved the inhibitory effect of BMF on BCL2L13-LC3B coupling, thereby restoring mitophagy. In addition, exosomal was required for BMF suppression and the superior activity of O-Exos. Together, these findings identify oxidative stress preconditioning as an effective strategy to enhance exosome potency against IDD. ACAN: aggrecan; BCL2L13: BCL2 like 13; BMF: Bcl2 modifying factor; BMSCs: bone marrow mesenchymal stem cells; BNIP3: BCL2 interacting protein 3; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; COL2A1: collagen type II alpha 1 chain; DHI: disc height index; FUNDC1: FUN14 domain containing 1; HO: hydrogen peroxide; IDD: intervertebral disc degeneration; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MMP3: matrix metallopeptidase 3; MRI: nuclear magnetic resonance imaging; N-Exos: exosomes derived from untreated BMSCs; NP: nucleus pulposus; O-Exos: exosomes derived from HO-preconditioned BMSCs; OCR: oxygen consumption rate; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; RT-qPCR: reverse transcription quantitative polymerase chain reaction; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; TEM: transmission electron microscopy; TNF/TNF-alpha: tumor necrosis factor; TOMM20: translocase of outer mitochondrial membrane 20; TP53: tumor protein p53; WT: wild type.
Chaperone-mediated autophagy reprograms heterogeneous subsets of activated macrophages in immune thrombocytopenia.
Xu Y, Zhang P, Wang L … +10 more , Wang H, Li Y, Mao J, Wang R, Wang W, Guo J, Cao J, Wang R, Hou M, Hou Y
Autophagy · 2026 Jun · PMID 42329073 · Publisher ↗
IFNG (interferon gamma)-activated macrophages contribute to accelerated clearance of platelets and excessive secretion of inflammatory cytokines in immune thrombocytopenia (ITP). In this study, we identified two distinct...
IFNG (interferon gamma)-activated macrophages contribute to accelerated clearance of platelets and excessive secretion of inflammatory cytokines in immune thrombocytopenia (ITP). In this study, we identified two distinct subpopulations of activated macrophages: phagocytic macrophages (M[IFNG]), which predominantly exhibit phagocytic activity, and inflammatory macrophages (M[IFNG]), characterized by their pro-inflammatory capacity. The M(IFNG) and M(IFNG) subsets were functionally disturbed in patients with ITP. Chaperone-mediated autophagy (CMA) deficiency in macrophages was discovered in ITP and has been reported to induce sustained inflammation. Furthermore, CMA interference enhanced pro-inflammatory function rather than phagocytic activity of macrophages . In parallel, macrophage-specific conditional (lysosome associated membrane protein 2A) knockout mice exhibited expansion and excessive cytokine release of M(IFNG). Restoring CMA restrains M(IFNG) subset and reprograms M(IFNG) subset via ALDH2 (aldehyde dehydrogenase 2 family member) in ITP. Here, anti-ITGB3/CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of ITP. CMA activation diminished the pro-inflammatory and phagocytic activity of activated macrophages and ameliorated thrombocytopenia in ITP mice. MeRIP-sequencing identified PTEN (phosphatase and tensin homolog) as a crucial activator for LAMP2A, exhibiting decreased mA methylation and subsequent downregulation, which indicated a potential mechanism underlying CMA deficiency in activated macrophages. In conclusion, restoring CMA restrains the M(IFNG) subset and reprograms the M(IFNG) subset via ALDH2 to raise platelet counts in ITP. Targeting CMA in activated primary human macrophages presents a promising therapeutic strategy to rapidly and sustainably increase platelet counts and restore immune balance in ITP. ALDH2: aldehyde dehydrogenase 2 family member; ALKBH5: alkB homolog 5, RNA demethylase; CCL: C-C motif chemokine ligand; CMA: chaperone-mediated autophagy; CSF1/M-CSF: colony stimulating factor 1; CUT&Tag: Cleavage Under Targets and Tagmentation; CXCL: C-X-C motif chemokine ligand; FBS: fetal bovine serum; FCGR/FcγR: Fc gamma receptor; HLA-DR: major histocompatibility complex, class II, DR; IFNG/IFN-γ: interferon gamma; IGF2R: insulin like growth factor 2 receptor; IL: interleukin; ITP: immune thrombocytopenia; LAMP2A: lysosome associated membrane protein 2A; mA: N-methyladenosine; MeRIP-seq: methylated RNA immunoprecipitation sequencing; METTL3: methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit; MFI: mean fluorescence intensity; mRNA: messenger RNA; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NLRP3: NLR family pyrin domain containing 3; NOS2/iNOS: nitric oxide synthase 2; PBMCs: peripheral blood mononuclear cells; PTEN: phosphatase and tensin homolog; PYCARD: PYD and CARD domain containing; STAT: signal transducer and activator of transcription; Th1: T-helper 1; TNF: tumor necrosis factor; WTAP: WT1 associated protein.
Mitophagy mitigates tau acetylation via the ULK1-NAD/SIRT1 axis in Alzheimer's disease.
Pan JP, Zhang J, Wang PJ … +2 more , Chen G, Fang EF
Autophagy · 2026 Jun · PMID 42323822 · Publisher ↗
Autophagy preserves neuronal integrity by clearing damaged proteins and other subcellular components, yet it declines with age and exacerbates in Alzheimer's disease (AD). Although autophagy reduces tauopathy, whether it...
Autophagy preserves neuronal integrity by clearing damaged proteins and other subcellular components, yet it declines with age and exacerbates in Alzheimer's disease (AD). Although autophagy reduces tauopathy, whether it can proactively restrict early tau pathology via post-translational modifications (PTMs) has remained unclear. In a recent paper, we have identified a mitophagy-based metabolic signaling mechanism linking the autophagy-initiating kinase Unc-51-like autophagy activating kinase 1 (ULK1) to the inhibition of pathogenic tau acetylation via the ULK1-NAD/SIRT1 axis. Analyses of human biofluidic to postmortem and transcriptomic data reveal an age-associated decline of ULK1; this situation gets worse in AD with the extent of ULK1 reduction positively correlates with Tau-based Braak stage progression, consistent with a bidirectional vicious cycle in which pathological tau disrupts mitochondrial homeostasis and impairs autophagy. Restoring ULK1-dependent mitophagy breaks this cycle in the upstream: in the hTau.P301S mice, ULK1 overexpression reduces ac‑tauK174 leading to reduced tau pathology and improved cognition. Mechanistically, ULK1 activates PINK1- and FUNDC1- as well as AMBRA1-dependent mitophagy to eliminate damaged mitochondria, restore bioenergetics, and elevate intracellular NAD, which activates the deacetylase SIRT1 to directly deacetylate tau at Lys174. Pharmacological ULK1 activation with a small molecule Rac‑BL‑918 phenocopies these protective effects in a mitophagy- and SIRT1-dependent manner. Collectively, our recent findings position mitophagy as a metabolic signaling hub that couples mitochondrial turnover to NAD/SIRT1 activity to shape neuronal tau PTMs, supporting ULK1-mitophagy activation as an upstream strategy to limit tauopathy before overt aggregation.
EGR1 mediates neuronal damage via suppressing HIF1A-induced mitophagy following traumatic brain injury.
Hou X, Zhang D, Sang X … +15 more , Peng C, Chen W, Xu J, Ye Y, Guo Y, Shi H, Yang C, Cai H, Wang Y, Chu G, Xu H, Lv L, Jin H, Wang C, Qu X
Autophagy · 2026 Jun · PMID 42323821 · Publisher ↗
Traumatic brain injury (TBI) remains a leading cause of neurological morbidity and mortality, characterized by complex pathophysiological cascades. Here, we investigate the role of the transcription factor EGR1 (early gr...
Traumatic brain injury (TBI) remains a leading cause of neurological morbidity and mortality, characterized by complex pathophysiological cascades. Here, we investigate the role of the transcription factor EGR1 (early growth response 1) in modulating mitochondrial homeostasis via the HIF1A (hypoxia inducible factor 1, alpha subunit)-BNIP3 (BCL2/adenovirus E1B interacting protein 3) axis following TBI. Using integrated transcriptomic and epigenomic analyses, we identified EGR1 as a critical regulator of TBI pathology, with its expression acutely upregulated in neurons post-injury. Genetic ablation of in mice significantly reduced neuronal apoptosis, preserved dendritic integrity, and ameliorated cognitive and sensorimotor deficits. Mechanistically, chromatin immunoprecipitation and luciferase assays revealed that EGR1 directly binds to the promoter, repressing its transcription. Loss of EGR1 enhanced HIF1A-BNIP3-mediated mitophagy, reducing mitochondrial dysfunction and oxidative stress both and . Conversely, silencing HIF1A or BNIP3 abrogated the neuroprotective effects of EGR1 deficiency. These findings establish a novel EGR1-HIF1A-mitophagy signaling axis as a key determinant of TBI outcomes, highlighting EGR1 as a potential therapeutic target.: AAV: adeno-associated virus; ACTB/β-actin: actin, beta; AIF1/IBA1: allograft inflammatory factor 1; BAF: bafilomycin A1; BNIP3: BCL2/adenovirus E1B interacting protein 3; CCI: controlled cortical impact; COX8: cytochrome c oxidase subunit 8; CUT&Tag: cleavage under targets and tagmentation; DAPI: 4,'6-diamidino-2-phenylindole; DEGs: differentially expressed genes; eGFP: enhanced green fluorescent protein; EGR1: early growth response 1; GFAP: glial fibrillary acidic protein; GO: gene ontology; GSEA: gene set enrichment analysis; HCQ: hydroxychloroquine; HIF1A/HIF-1α: hypoxia inducible factor 1, alpha subunit; IGV: integrative genomics viewer; KEGG: Kyoto encyclopedia of genes and genomes; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; Lv: lentivirus; MAP2: microtubule-associated protein 2; mCherry: monomeric cherry fluorescent protein; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MUT: mutant; MWM: Morris water maze; NAB1: Ngfi-A binding protein 1; NAB2: Ngfi-A binding protein 2; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; OGD: oxygen-glucose deprivation; OLIG2: oligodendrocyte transcription factor 2; PBS: phosphate-buffered saline; PECAM1/CD31: platelet/endothelial cell adhesion molecule 1; PFA: paraformaldehyde; PPI: protein-protein interaction; Puro: puromycin; ROI: region of interest; ROS: reactive oxygen species; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TBI: traumatic brain injury; TOMM20: translocase of outer mitochondrial membrane 20; TSA: tyramide signal amplification; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VDAC1: voltage-dependent anion channel 1; WT: wild-type.
Cholesterol-driven sequestration of RETREG1/FAM134B regulates ERphagy and STING1 innate immunity.
Govind CK, Klionsky DJ
Autophagy · 2026 Jul · PMID 42318785 · Full text
The endoplasmic reticulum (ER) is a hub for several essential functions, including lipid metabolism, macroautophagy/autophagy, and innate immune signaling. Excess ER generated during a stress response is degraded by a se...
The endoplasmic reticulum (ER) is a hub for several essential functions, including lipid metabolism, macroautophagy/autophagy, and innate immune signaling. Excess ER generated during a stress response is degraded by a selective type of autophagy known as ERphagy/reticulophagy. A recent study provides a mechanism by which cholesterol levels regulate ERphagy, STING1 activation, and cholesterol biosynthesis. Elevated ER cholesterol levels suppress ERphagy by reducing RETREG1/FAM134B interactions with the autophagy-related protein MAP1LC3/LC3 and the lysosomal protein LAMP2. The study shows that cholesterol directly binds to RETREG1 and SCAP, facilitating the formation of the RETREG1-SCAP complex. Sequestration of RETREG1 in this manner prevents it from performing its ERphagy functions. Furthermore, RETREG1 also interacts with STING1 and is important for its activation in response to viral infections. SCAP-RETREG1 complex formation also reduces the STING1 response. Thus, this study links lipid metabolism, innate immunity, and autophagy, emphasizing a central role for cholesterol in these processes.
Optineurin, an autophagy adaptor, stabilizes Rictor to maintain Akt/mTOR signaling and antigen presentation.
Kadam R, Shukla D
Autophagy · 2026 Jun · PMID 42316951 · Publisher ↗
Optineurin (OPTN) is widely recognized as a multifunctional selective autophagy receptor involved in cargo turnover. However, our recent findings uncover an unexpected function of OPTN that challenges the conventional vi...
Optineurin (OPTN) is widely recognized as a multifunctional selective autophagy receptor involved in cargo turnover. However, our recent findings uncover an unexpected function of OPTN that challenges the conventional view of autophagy adaptors. In dendritic cells (DCs), OPTN binds to and stabilizes Rictor, a key component of the mTORC2 complex. Loss of OPTN leads to depletion of Rictor, reduced Akt2 activity, and activation of the mTORC1/p70S6K1 pathway, culminating in enhanced phosphorylation of STAT3 at Ser727. Activated STAT3 transcriptionally induces the E3 ubiquitin ligase MARCH1, which promotes MHC II internalization, resulting in a striking inverse relationship between MARCH1 and MHC II expression in Optn-deficient cells. Together, these findings identify an unexpected signaling function of OPTN, independent of its canonical autophagy activities. By stabilizing Rictor and maintaining mTORC2-Akt2 signaling, OPTN links a classical autophagy adaptor to the regulation of antigen presentation and adaptive immunity. More broadly, our findings raise the possibility that selective autophagy receptors preserve cellular homeostasis not only through cargo clearance but also through context-dependent, non-degradative regulation of protein stability and signaling networks.: OPTN: Optineurin; mTORC1: mammalian target of rapamycin complex 1; mTORC2: mammalian target of rapamycin complex 1; Rictor: Rapamycin-Insensitive Companion of mTOR.
Dysregulation of a novel autophagosome-mitochondria contact contributes to tauopathy-related neurodegeneration by disrupting autophagy.
Jia N, Zuo Y, Guan H … +2 more , Rajapaksha G, Cai Q
Autophagy · 2026 Jun · PMID 42316849 · Publisher ↗
Beyond their role in energy production, mitochondria also interact with other organelles through forming membrane contacts that serve as central hubs of cellular metabolism and signaling. Aberrant mitochondria-organelle...
Beyond their role in energy production, mitochondria also interact with other organelles through forming membrane contacts that serve as central hubs of cellular metabolism and signaling. Aberrant mitochondria-organelle communication has been implicated in various neurodegenerative diseases, but the underlying mechanisms and their pathological consequences remain poorly understood. Here, we reveal that tauopathy synapses exhibit excessive tethering of autophagosome/autophagic vacuole (AV)-mitochondria (Mito) contacts, driven by mitochondrial bioenergetic deficit-induced hyperactivity of adenosine monophosphate-activated protein kinase (AMPK) that results in accelerated turnover of the contact release factor TBC1D15. Such defects consequently disrupt autophagy-mediated clearance of MAPT/tau by preventing AV retrograde transport. Strikingly, elevating TBC1D15 levels normalizes AV-Mito contact dynamics and restores autophagy activity, thereby mitigating MAPT/tau pathology and ameliorating neurodegeneration and cognitive impairment in tauopathy mice. Together, these findings establish bioenergetic deficits and the resulting AV-Mito hyper-tethering as a critical mechanism driving autophagy dysfunction and pathological MAPT/tau buildup in tauopathy neurons and highlight TBC1D15-modulated AV-Mito contact release and autophagy as promising therapeutic targets for tauopathies, including Alzheimer disease. AAV, adeno-associated virus; AD, Alzheimer disease; AMPK, adenosine monophosphate-activated protein kinase; AV, autophagosome/autophagic vacuole; CLEM, correlative light and electron microscopy; cryo-ET, cryo-electron tomography; FTD, Frontotemporal dementia; GAP, GTPase-activating protein; Mito, mitochondria; NFT, neurofibrillary tangle; OE, overexpression; Phospho-MAPT/tau, phosphorylated MAPT/tau; SQSTM1/p62, sequestosome 1; TEM, transmission electron microscopy; Tg, transgenic.
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