Autophagy [JOURNAL]
Sun
200 papers
Cytosol-dwelling bacteria engage in a ubiquitination race to avoid antibacterial autophagy.
Popelka H, Klionsky DJ
Autophagy · 2026 Apr · PMID 41877381 · Full text
One of the defense mechanisms of host cells against bacterial pathogens is antibacterial macroautophagy/autophagy that relies on ubiquitination of a pathogen for recognition by specific receptors that deliver the pathoge...
One of the defense mechanisms of host cells against bacterial pathogens is antibacterial macroautophagy/autophagy that relies on ubiquitination of a pathogen for recognition by specific receptors that deliver the pathogen to phagophores. RNF213 is an E3 ligase that mediates ubiquitination of lipopolysaccharides (LPS) on bacteria dwelling in the host cytosol. However, one type of cytosol-invading bacteria, , evolved a mechanism through which it can avoid LPS ubiquitination. employs IpaH1.4, an effector protein with E3 ligase activity that ubiquitinates RNF213 for proteasomal degradation. Here, we discuss a study that discovered this strategy, and revealed by cryo-EM that the IpaH1.4 leucine-rich repeat recognizes and binds the RNF213 RING domain. The mass spectrometry data showed that IpaH1.4 targets several other RING-containing E3 ligases implicated in inflammation and immunity, which opens a new field for xenophagy.: cryo-EM, cryo-electron microscopy; LPS, lipopolysaccharide; LRR, leucine-rich repeat; LUBAC, linear ubiquitin chain assembly complex; NEL, novel E3 ligase; OPTN, optineurin.
A localization gate licenses chaperone-mediated autophagy of SNAI (snail) to restrain epithelial-mesenchymal transition competence in breast cancer.
Ryu KJ, Kim M, Yoo J
Autophagy · 2026 Jun · PMID 41870329 · Full text
SNAI (snail family transcriptional repressor) is a master regulator of epithelial-mesenchymal transition (EMT), yet its protein abundance varies markedly across breast cancer subtypes and cellular states. We identify SNA...
SNAI (snail family transcriptional repressor) is a master regulator of epithelial-mesenchymal transition (EMT), yet its protein abundance varies markedly across breast cancer subtypes and cellular states. We identify SNAI as a bona fide substrate of chaperone-mediated autophagy (CMA) and propose a localization gate model in which nucleocytoplasmic trafficking dictates CMA accessibility. Macroautophagy inhibition stabilizes SQSTM1/p62 but does not alter SNAI levels, whereas depletion of the CMA chaperone HSPA8/HSC70 or the lysosomal receptor LAMP2A increases SNAI protein levels and extends its half-life. A CMA-resistant SNAI mutant fails to bind HSPA8-LAMP2A, is stabilized, and enhances EMT outputs, including migration, invasion, and lung colonization. In triple-negative breast cancer cells, SNAI is predominantly nuclear at baseline and thus inaccessible to CMA. Serum starvation promotes nuclear export, enabling cytosolic exposure and CMA-dependent degradation, which is blocked by leptomycin B. These findings connect selective autophagy to compartmental shielding and suggest that promoting cytosolic exposure and/or enhancing CMA capacity may attenuate SNAI-driven EMT competence.
Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
Thayer JA, Narendra DP
Autophagy · 2026 Jun · PMID 41866905 · Full text
Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, wh...
Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, whether diverse forms of mitochondrial damage activate the PINK1-PRKN pathway through a unified mechanism. Recently, we demonstrated that loss of mitochondrial membrane potential (MMP) leads to the stabilization and activation of PINK1 under a wide range of mitochondrial stressors, including mitochondrial protein misfolding. Mechanistically, we suggest that the MMP is required at a key step of PINK1 import into mitochondria, in which PINK1 is transferred between the translocases of the outer and inner mitochondrial membranes. Consistent with this model, retention of active PINK1 of the outer membrane requires the translocase of the outer mitochondrial membrane (TOMM) complex, whereas import of PINK1 from the outer to inner membrane requires the TIMM23 (translocase of inner mitochondrial membrane 23) complex. Notably, chronic disruption of the TIMM23 complex is sufficient to stabilize active PINK1 in the TOMM complex, phenocopying MMP loss. Together, our findings suggest PINK1 primarily senses catastrophic drops in a mitochondrion's MMP: a dead-end for the mitochondrion's continued biogenesis.
8 and protein ATG8ylation - more than just nother a?
Gerth F, Kosol S, Aley N … +2 more , Agrotis A, Ketteler R
Autophagy · 2026 Jul · PMID 41860121 · Full text
Since its discovery as a key component of the autophagosome membrane, the small ubiquitin-like protein ATG8 and its mammalian homologs (ATG8s) have garnered a lot of attention. Many researchers use it as a marker for aut...
Since its discovery as a key component of the autophagosome membrane, the small ubiquitin-like protein ATG8 and its mammalian homologs (ATG8s) have garnered a lot of attention. Many researchers use it as a marker for autophagosome number, size and composition. A lot of research has focussed on its function in forming complexes required for autophagosome-lysosome fusion or generally, its interaction with other proteins via the ATG8-family interacting motif/AIM. Many additional functions have been discovered, for instance in non-canonical autophagy processes and in the nucleus. The list of known functions of ATG8 are ever expanding, and, most recently, evidence has emerged that, similar to ubiquitin, ATG8 can modify proteins by covalent attachment to a lysine residue (protein ATG8ylation). In this review, we aim to summarize the current literature on protein ATG8ylation and highlight the currently known substrates. We propose strategies to investigate this modification and provide an outlook for its possible cellular function.: ATG: autophagy related; DUBs: de-ubiquitinating enzymes; GABARAPL: GABA type A receptor associated protein like; GIR: GABARAP-interacting region; LIR: LC3-interacting region; MAP1LC3: microtubule associated protein 1 light chain 3; RMSD: root mean square; UBL: ubiquitin-like; UPS: ubiquitin-proteasome-system.
ATG2A connects lipid droplets and the ER to regulate lipid storage.
Elhan H, Korfhage JL, Melia TJ … +1 more , Thiam AR
Autophagy · 2026 Jun · PMID 41848282 · Full text
The endoplasmic reticulum (ER) must carefully regulate the levels of nonmembrane lipids such as diacylglycerol (DAG), phosphatidic acid (PA), and triacylglycerol (TAG) to maintain membrane integrity and prevent lipotoxic...
The endoplasmic reticulum (ER) must carefully regulate the levels of nonmembrane lipids such as diacylglycerol (DAG), phosphatidic acid (PA), and triacylglycerol (TAG) to maintain membrane integrity and prevent lipotoxic stress. While ATG2A is well known as a lipid transfer protein essential for autophagosome formation, its role at lipid droplet (LD) contact sites has remained unclear. In our recent work, we show that ATG2A functions beyond its typical role in autophagy as a key regulator of lipid storage, transferring DAG, TAG, and PA from the ER to LDs and recruiting the TAG synthesis enzyme DGAT2 to promote LD expansion. Without ATG2A, lipids accumulate in the ER, leading to smaller, more numerous nucleated LDs rather than proper growth. Notably, ATG2A-mediated DAG transfer recruits DGAT2 to LD surfaces, enabling local TAG synthesis that prevents nonmembrane lipid accumulation in the ER. This cooperative process reveals ATG2A's dual role in both autophagy and lipid storage, highlighting an unexpected link between autophagy machinery and lipid storage.
Lipophagy fuels phosphatidylcholine synthesis for Newcastle disease virus replication.
Yang M, Chen J, Su X … +8 more , Kan X, Tan L, Song C, Qiu X, Liao Y, Yu S, Ding C, Sun Y
Autophagy · 2026 Jun · PMID 41810751 · Full text
Lipid droplets (LDs) are dynamic organelles that store neutral lipids and maintain lipid homeostasis. Many viruses exploit LDs as replication platforms or lipid sources, but their role in supplying membrane lipids for vi...
Lipid droplets (LDs) are dynamic organelles that store neutral lipids and maintain lipid homeostasis. Many viruses exploit LDs as replication platforms or lipid sources, but their role in supplying membrane lipids for viral assembly remains unclear. Newcastle disease virus (NDV), an enveloped RNA virus with oncolytic potential, extensively remodels host metabolism, yet its impact on LD lipid mobilization is unknown. Here, we show that NDV reprograms host lipid metabolism via SQSTM1/p62-dependent lipophagy, selectively degrading triglycerides (TAGs) enriched in unsaturated fatty acids (UFAs). Lipidomics revealed concurrent depletion of UFA-containing triglycerides (UFA-TAGs) and UFA-containing phosphatidylcholines (UFA-PCs) during infection. Inhibition of lipophagy blocked LD degradation, reduced viral replication, and suppressed UFA-PC formation. Isotope tracing demonstrated that lipophagy-derived UFAs are incorporated into phosphatidylcholines (PCs) via the Kennedy pathway, whereas β-oxidation was dispensable. UFA supplementation rescued viral replication under lipophagy blockade and promoted virus-like particle (VLP) release, indicating that UFA-PCs facilitate viral budding. These findings uncover a distinct NDV strategy linking lipophagy-driven UFA release to phospholipid synthesis and membrane remodeling, revealing a lipid-based metabolic vulnerability for antiviral and oncolytic interventions.: AP: autophagosome; ATG: autophagy related; ATP: adenosine triphosphate; CQ: chloroquine; EGFP: enhance green fluorescent protein; FFA: free fatty acid; HN: Hemagglutinin-Neuraminidase; LA: linoleic acid; LD: lipid droplet; LIPA: lipase A, lysosomal acid type; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NDV: newcastle disease virus; NP: nucleoprotein; OA: oleic acid; PA: palmitic acid; PC: phosphatidylcholine; PLIN2/ADRP: perilipin 2; PNPLA2/ATGL: patatin like phospholipase domain containing 2; POA: palmitoleic acid; SFA: saturated fatty acid; TAG: triglyceride; UFA: unsaturated fatty acid; UFA-PC: UFA-containing phosphatidylcholine; VLP: virus-like particle.
Neutralization of DBI/ACBP for the prevention of ciliopathy-associated obesity.
Corral Nieto Y, Kroemer G, Bravo-San Pedro JM
Autophagy · 2026 May · PMID 41803642 · Full text
Obesity is a feature of only a subset of ciliopathies, including Alström syndrome, a rare genetic disorder caused by ALMS1 deficiency. In our recent work, we applied integrative multi-omics network analysis to one of the...
Obesity is a feature of only a subset of ciliopathies, including Alström syndrome, a rare genetic disorder caused by ALMS1 deficiency. In our recent work, we applied integrative multi-omics network analysis to one of these ciliopathies that develop with obesity, the -deficient mouse model and identified DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) as a central driver of ciliopathy-associated obesity. We found that ALMS1 deficiency induces early hepatic dyslipidemia accompanied by impaired macroautophagy/autophagy and pathological accumulation of DBI/ACBP, preceding overt obesity. Importantly, prophylactic DBI/ACBP neutralization with monoclonal antibodies prevents weight gain and metabolic alterations without restoring autophagic markers, indicating that DBI/ACBP acts as an obesogenic effector downstream of, or parallel to, defective autophagy. These findings position DBI/ACBP as a metabolically relevant autophagy-associated regulator in ciliopathy and suggest that therapeutic benefit can be achieved by targeting autophagy-linked effectors without directly correcting autophagic flux. This punctum discusses our results in the context of hepatic autophagy and lipid metabolism, highlighting DBI/ACBP as a mechanistic link between ciliary dysfunction, altered autophagy, and metabolic disease.
Impaired mitophagy contributes to osteogenesis and mineralization disorders in fibrous dysplasia.
Ling Z, Hu L, Jin S … +7 more , Ling F, Jin C, Yuan X, Chen X, Xie H, Jiang H, Fu Y
Autophagy · 2026 Mar · PMID 41803635 · Publisher ↗
Fibrous dysplasia (FD) is a bone mesenchymal stromal cells (BMSCs)-derived disorder caused by gene mutation, characterized by excessive fibrous tissue proliferation in bone and the formation of immature trabecular bone....
Fibrous dysplasia (FD) is a bone mesenchymal stromal cells (BMSCs)-derived disorder caused by gene mutation, characterized by excessive fibrous tissue proliferation in bone and the formation of immature trabecular bone. Although impaired osteogenesis of BMSCs is central to FD pathogenesis, the underlying mechanism remains largely elusive. Here we demonstrate that hyperactivation of the cAMP-PRKA/PKA signaling axis disrupts mitochondrial homeostasis through impaired mitophagy, ultimately leading to diminished amorphous calcium phosphate (ACP) secretion and consequent mineralization failure in FD. Mechanistically, in FD BMSCs, PRKA activation inhibits DNM1L/DRP1 recruitment to mitochondria through phosphorylation at S637, thereby suppressing mitochondrial fission. Consequently, excessive mitochondrial fusion leads to an elevated mitochondrial membrane potential, impaired mitophagy, and diminished ACP release. Collectively, our findings reveal a novel signaling nexus linking cAMP-PRKA signaling, mitochondrial dynamics, and biomineralization processes in FD pathogenesis, providing critical insights into the molecular basis of this disorder.: ACP: amorphous calcium phosphate; ALPL: alkaline phosphatase, biomineralization associated; Baf A1: bafilomycin A1; BGLAP/osteocalcin: bone gamma-carboxylglutamate protein; BMD: bone mineral density; BMSCs: bone marrow stromal cells; BV/TV: bone volume/tissue volume; cAMP: cyclic adenosine monophosphate; COL1: collagen type I; COX4/COXIV: cytochrome c oxidase subunit 4; CsA: cyclosporin A; CT: computerized tomography; Cyto: cytoplasm; DAPI: diamino phenylindole; DEPs: differentially expressed proteins; DNM1L/DRP1: dynamin 1 like; ECL: electrochemiluminescence; ECM: extracellular matrix; FBS: fetal bovine serum; FCCP: carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone; FD: fibrous dysplasia; GNAS/guanine nucleotide-binding protein alpha-stimulating activity peptide: GNAS complex locus; GTPase: guanosine triphosphatase; HSPD1/HSP60: heat shock protein family D (Hsp60) member 1; Lyso: lysosome; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Mdivi: mitochondrial division inhibitor 1; MEMα: minimum essential medium α; MFN1: mitofusin 1; MFN2: mitofusin 2; Mito: mitochondria; MMP: mitochondrial membrane potential; MOI: multiplicity of infection; MV: matrix vesicle; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PHEX: phosphate regulating endopeptidase X-Linked; PHOSPHO1: phosphoethanolamine/phosphocholine phosphatase 1; PINK1: PTEN induced kinase 1; PRKA/protein kinase A: protein kinase cAMP-activated; PVDF: polyvinylidene fluoride; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SEM: scanning electron microscopy; SOST: sclerostin; SP7/Osterix: Sp7 transcription factor; TA9: tyrphostin A9; Tb.N: trabecular. number; Tb.Sp: trabecular. separation; Tb.Th: trabecular. thickness; TEM: transmission electron microscopy; TMRM: tetramethylrhodamine; UA: urolithin A.
Lipotoxic hepatocyte-derived -enriched small extracellular vesicles activate hepatic stellate cells to promote hepatic fibrosis.
Yang F, Chen Y, Wang Y … +5 more , Zheng G, Abouelnazar F, Fan L, Wang Y, Yan Y
Autophagy · 2026 Mar · PMID 41795680 · Publisher ↗
Metabolic dysfunction-associated steatohepatitis (MASH) serves as a primary contributor to liver fibrosis, cirrhosis, and hepatocellular carcinoma, yet specific diagnostic markers and therapeutic targets remain unavailab...
Metabolic dysfunction-associated steatohepatitis (MASH) serves as a primary contributor to liver fibrosis, cirrhosis, and hepatocellular carcinoma, yet specific diagnostic markers and therapeutic targets remain unavailable. This study elucidates the molecular mechanism by which UBQLN1 (ubiquilin 1) promotes MASH-related liver fibrosis by regulating small extracellular vesicles (sEVs) secretion and the functionality of the lysosome-mitochondria axis, as well as its clinical significance. Analysis of a multicenter cohort ( = 150) demonstrated significantly elevated UBQLN1 levels in both serum and serum-derived sEV from MASH patients, exhibiting diagnostic accuracies of 0.89 and 0.95, respectively. Furthermore, increased UBQLN1 was observed in mouse models of MASH, hiPSCs-derived human liver organoids, and oleic acid and palmitic acid injured hepatocytes (lipotoxic hepatocytes). Mechanistically, lipotoxic stress induces O-GlcNAcylation at the T277 site of UBQLN1 OGT (O-GlcNAc transferase), which competitively inhibits its phosphorylation, consequently reducing ubiquitin-mediated degradation. Hepatocyte UBQLN1 facilitates the secretion of sEVs by regulating LAMP1-mediated fusion of multivesicular bodies (MVBs) with lysosomes. Subsequently, sEVs containing UBQLN1 regulate the activation of hepatic stellate cells by degrading the V-ATPase subunit ATP6V1B2 through E54D-dependent ubiquitin ligase activity, thereby inhibiting lysosomal acidification and mitophagy. Moreover, hepatic-specific knockdown of or hepatocyte-specific knockdown of significantly alleviates fibrosis and metabolic disorders in MASH mice. This study elucidates the critical role of the post-translational modification regulatory network of UBQLN1 in the progression of MASH and proposes its translational potential as an integrated therapeutic target, providing a theoretical basis for the development of sEV-based intervention strategies. ATP6V1B2 ATPase H+ transporting V1 subunit B2; Co-IP: co-immunoprecipitation; CCL4: carbon tetrachloride; ELISA: enzyme linked immunosorbent assay; GOT1/AST: glutamic-oxaloacetic transaminase; GPT/ALT: glutamic-pyruvic transaminase; hiPSCs: human induced pluripotent stem cells; HFD: high-fat diet; HFHC: high-fat and high-cholesterol diet; HSCs: hepatic stellate cells; LAMP1: lysosomal associated membrane protein 1; LTH-sEV: lipotoxic hepatocyte-derived small extracellular vesicles; LSECs: liver sinusoidal endothelial cells; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MVBs: multivesicular bodies; MASH: metabolic dysfunction-associated steatohepatitis; N-sEV: normal hepatocyte-derived sEV; OGT: O-linked N-acetylglucosamine (GlcNAc) transferase; O-GlcNAc: O-linked-β-D-N-acetylglucosamine; PAOA: oleic acid and palmitic acid; sEV: small extracellular vesicle; UBQLN1: ubiquilin 1.
FUNDC1-dependent mitophagy determines axon regeneration capacity.
Li W, Liu Y, Liu R … +7 more , Fan Y, Liu J, Guo Y, Hu Z, Liu L, Chen Q, Zhou B
Autophagy · 2026 Jun · PMID 41795666 · Full text
Neuronal axon regeneration is a complex and coordinated reorganization process that requires the involvement of mitochondria. Here, we demonstrated that FUNDC1 (FUN14 domain containing 1)-mediated mitophagy played a cruc...
Neuronal axon regeneration is a complex and coordinated reorganization process that requires the involvement of mitochondria. Here, we demonstrated that FUNDC1 (FUN14 domain containing 1)-mediated mitophagy played a crucial role in determining the intrinsic capacity for axonal regrowth and peripheral nerve recovery. We found that acute nerve injury resulted in the accumulation of impaired mitochondria at the axonal injury site, accompanied by an increase in the expression of the mitophagy receptor FUNDC1. Strikingly, overexpression of FUNDC1 enhanced axonal regeneration both in vitro and in vivo, likely by maintaining a healthy mitochondrial population through mitophagy. Similarly, treatment with urolithin A (UA), a natural mitophagy inducer, promoted axon regrowth after injury. Conversely, deletion impaired regeneration, an effect reversed by reintroducing wild type (WT) FUNDC1 in neurons but not an MAP1LC3B/LC3 (microtubule associated protein 1 light chain 3 beta)-interacting region (LIR) mutant. Metabolic profiling further demonstrated that FUNDC1-mediated mitophagy drives dorsal root ganglion (DRG) neurons regeneration through enhanced carnosine biosynthesis. Mechanistically, sciatic nerve injury (SNI) in transgenic (TG) mice upregulated NRF1 (nuclear respiratory factor 1) and PPARGC1A/PGC-1α (PPARG coactivator 1 alpha), which stimulated mitochondrial biogenesis and activated (carnosine synthase 1) transcription. This increased carnosine biosynthesis, aiding peripheral nerve recovery through its antioxidant effects. Our findings highlighted FUNDC1-mediated mitophagy as a key mechanism in nerve regeneration, linking mitochondrial quality control, metabolic adaptation, and nerve regeneration.: Δψm: mitochondrial membrane potential; DIV: days in vitro; DRG: dorsal root ganglion; KO: knockout; LIR: LC3-interacting region; P60: postnatal day 60; PNS: peripheral nervous system; PSI: post sciatic nerve injury; ROS: reactive oxygen species; SD: standard deviation; SNI: sciatic nerve injury; TEM: transmission electron microscopy; TG: transgenic; TMRE: tetramethylrhodamine ethylester; UA: urolithin A; WT: wild type.
The TBCK-PPP1R21-FERRY3/C12orf4 complex: a RAB5-GAP brake essential for endo-lysosomal homeostasis.
Chen Y, Xu X, Zheng Y … +2 more , Wang H, Wang C
Autophagy · 2026 May · PMID 41789809 · Full text
TBCK syndrome is a severe neurodevelopmental disorder characterized by hypotonia, intellectual disability, and progressive neurodegeneration. While the gene has been implicated in MTOR signaling, its primary molecular f...
TBCK syndrome is a severe neurodevelopmental disorder characterized by hypotonia, intellectual disability, and progressive neurodegeneration. While the gene has been implicated in MTOR signaling, its primary molecular function has remained controversial. In a recent study, we identify TBCK as the catalytic core of a heterotrimeric complex comprising TBCK, PPP1R21, and FERRY3/C12orf4. This complex functions as a specific GTPase-activating protein (GAP) for RAB5. deficiency or missense mutations of its key residues in the RABGAP-TBC domain lead to constitutive RAB5 hyperactivation, which blocks the transition from early to late endosomes and results in the formation of massively enlarged RAB5-positive endosomes. Furthermore, this RAB5 hyperactivation drives the constitutive activation of the PIK3C3/VPS34 complex. These defects culminate in a failure of lysosomal enzyme delivery and a secondary collapse of macroautophagic/autophagic flux. These findings redefine TBCK syndrome as a primary disorder of endosomal dynamics and highlight the TBCK-PPP1R21-FERRY3 axis as a critical "brake" for maintaining neuronal homeostasis.
Autocrine SFRP2 (secreted frizzled related protein 2) enhances lung myofibroblast fibrogenic activity by suppressing PINK1-mediated mitophagy initiation.
Lin Y, Lei T, Jia Y … +5 more , Yao M, Wang X, Huang S, Wang Z, Lai X
Autophagy · 2026 Jun · PMID 41789512 · Full text
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease driven by persistent activation of pulmonary myofibroblasts, but the regulatory mechanisms sustaining this pathological state remain incompletely u...
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease driven by persistent activation of pulmonary myofibroblasts, but the regulatory mechanisms sustaining this pathological state remain incompletely understood. Using single-cell RNA sequencing (scRNA-seq), we identified SFRP2 (secreted frizzled related protein 2) as a critical mediator of profibrotic myofibroblasts in IPF lungs. Functional studies revealed that SFRP2 acted in an autocrine manner to promote myofibroblast activation and extracellular matrix (ECM) production. Mechanistically, SFRP2 activated FZD5-mediated non-canonical WNT-Ca signaling, leading to PPP3/calcineurin-dependent translocation of PINK1 from the outer to the inner mitochondrial membrane (IMM), where it was degraded, thereby inhibiting PINK1-mediated mitophagy. Furthermore, therapeutic intervention with AAV6-sh, SFRP2-neutralizing antibody, or the autophagy inducer rapamycin significantly ameliorated lung fibrosis in bleomycin (BLM)-induced mouse models. Our results define a novel autocrine SFRP2-mitophagy regulatory axis that perpetuates myofibroblast activation and represents a promising therapeutic target for pulmonary fibrosis.: AAV: adeno-associated virus; BLM: bleomycin; CQ: chloroquine; ECM: extracellular matrix; FZD5: frizzled class receptor 5; H&E: hematoxylin and eosin; IHC: immunohistochemical; IMM: inner mitochondrial membrane; IPF: idiopathic pulmonary fibrosis; Micro-CT: micro-computed tomography; mtROS: mitochondrial reactive oxygen species; PMLFs: primary mouse lung fibroblasts; qPCR: quantitative real-time PCR; scRNA-seq: single-cell RNA sequencing; SFRP2: secreted frizzled related protein 2; TEM: transmission electron microscopy; ∆Ψm: mitochondrial membrane potential.
α-hemolysin targets LGALS3 (galectin 3) to promote intracellular survival of via lysosomal disruption and autophagy inhibition.
Zhang Y, Zhao Z, Han P … +14 more , Qi J, Zhang M, Wang L, Meng Y, Li J, Yang Y, Chen L, Zhang J, Gu J, Luo P, Zhang W, Sun L, Zou Q, Zeng H
Autophagy · 2026 Jul · PMID 41787826 · Full text
Intracellular persistence caused by () is among the primary reasons for recurrence and difficulty in eradicating infections. In this study, we identify the secreted protein Hla (α-hemolysin) by as a key factor enablin...
Intracellular persistence caused by () is among the primary reasons for recurrence and difficulty in eradicating infections. In this study, we identify the secreted protein Hla (α-hemolysin) by as a key factor enabling its intracellular retention. We demonstrate that intracellular Hla secreted by inhibits lysosome degradation via disrupting lysosomal function, which sustains the survival and proliferation of within autophagosomes. Furthermore, we identify the interaction between Hla and intracellular LGALS3 (galectin 3) as crucial for sustaining intracellular survival of , resolve the structure of the Hla-LGALS3 complex, and identify the Loop 68-75 region of Hla as the key binding domain with LGALS3. Moreover, the interaction between Hla and LGALS3 influences the recruitment of PDCD6IP/ALIX (programmed cell death 6 interacting protein) to the damaged lysosomal surface, resulting in disruption of lysosomal degradative function. Our results highlight an unknown role of Hla in the intracellular survival of and suggest that interrupting the interaction between Hla and LGALS3 May be a potential therapeutic strategy for treating infections.Abbreviations: 3 MA: 3-methyladenine; AECII: alveolar epithelial cells II; Agr: accessory gene regulator; ATG13: autophagy related 13; Baf A: bafilomycin A; BLI: biolayer interferometry; CFU: colony-forming units; ClfA: clumping factor A; Co-IP: co-immunoprecipitation; CRD: carbohydrate recognition domain; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; FnbA: fibronectin-binding protein A; FnbB: fibronectin-binding protein B; Hla: α-hemolysin; IP-MS: immunoprecipitation-mass spectrometry; LGALS3: galectin 3; LLoMe: L-leucyl-L-leucine methyl ester hydrobromide; LMP: lysosomal-membrane permeabilization; MOI: multiplicity of infection; PDCD6IP/ALIX: programmed cell death 6 interacting protein; : ; SPA: staphylococcal protein A; SSPA: staphylococcal surface protein A; TEM: transmission electron microscopy; TRAF3: TNF receptor associated factor 3; ULK1: unc-51 like autophagy activating kinase 1.
Duloxetine ameliorates cerebral ischemic injury by inhibiting autophagy.
Viotti A, Molinaro C, Perego J … +14 more , Fossaghi A, Parravicini C, Lauranzano E, Borreca A, Piccoli M, Anastasia L, Manenti S, Finardi A, Mandelli A, Matteoli M, Eberini I, Panina P, Martino G, Muzio L
Autophagy · 2026 Jun · PMID 41787744 · Full text
Ischemic stroke is a severe medical condition characterized by diminished blood flow to the brain, resulting in a shortage of oxygen and nutrients. During ischemia, neurons surrounding the cerebral infarct initiate macro...
Ischemic stroke is a severe medical condition characterized by diminished blood flow to the brain, resulting in a shortage of oxygen and nutrients. During ischemia, neurons surrounding the cerebral infarct initiate macroautophagy. However, the implications of this activation for neuronal cell survival are still debated. The identification of new autophagy modulators could aid in understanding autophagy's role in brain ischemia and lay the groundwork for innovative therapeutic strategies aimed at minimizing brain damage in this life-threatening neurological emergency. In this study, we developed a robust and sensitive screening platform to identify autophagy modulators from a library of bioactive compounds. Selected compounds underwent further validation, leading to the identification of duloxetine, a Food and Drug Administration (FDA)-approved drug, as an effective autophagy inhibitor at low-micromolar concentrations. Following its original characterization, the molecule, a serotonin-norepinephrine re-uptake inhibitor (SNRI) family member, was subsequently tested in young and aged mice subjected to photothrombotic stroke. Our results demonstrated that duloxetine significantly reduced infarct size and improved locomotor performance in mice that had undergone a stroke. Similar protective effects were observed in transgenic mice lacking the autophagy gene (autophagy related 5) in SLC17A6/Vglut2 (solute carrier family 17 member 6) excitatory cortical neurons. Finally, we elucidated the underlying mechanism of action that involves duloxetine-mediated inhibition of TRPM2 (transient receptor potential cation channel subfamily M member 2) ion channels. Altogether, our findings suggest that early autophagy inhibition is neuroprotective in stroke, and duloxetine serves as an effective means of achieving this inhibition. AMPK - AMP-activated protein kinase; ATG5 - autophagy related 5; AVs - autophagic vacuoles; Baf -bafilomycin A; BBB - blood-brain barrier; BECN1 -beclin 1; CAMK2 -calcium/calmodulin dependent protein kinase II; cCASP3 -cleaved CASP3; cKO -conditional knockout; CNS -central nervous system; DMPK - drug metabolism and pharmacokinetics; DMSO -dimethyl sulfoxide; DIV - days ; DMEM - Dulbecco's modified Eagle's medium; FDA - Food and Drug Administration; FBS -fetal bovine serum; GFP -green fluorescent protein; GFAP -glial fibrillary acidic protein; HIF1A/HIF-1α - hypoxia inducible factor 1 subunit alpha; HMGCR - 3-hydroxy-3-methylglutaryl-CoA reductase; IHC - immunohistochemistry; I/R - ischemia-reperfusion; LAMP1 - lysosomal associated membrane protein 1; MAP1LC3B/LC3B -microtubule associated protein 1 light chain 3 beta; MCAO - middle cerebral artery occlusion; MFI -mean fluorescence intensity; MTT - 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide; ND -nutrient deprivation; NPCs -neural precursor cells; NVU -neuro-vascular unit; OGD - oxygen-glucose deprivation; PI - propidium iodide; PIKK - phosphatidylinositol 3-kinase-like; PRKDC/DNA-PKcs - protein kinase, DNA-activated, catalytic subunit; SQSTM1/p62 -sequestosome 1; PIK3C3/VPS34 - phosphatidylinositol 3-kinase catalytic subunit type 3; PK-hLC3 -pHluorin-mKate2-human LC3; PLP1 - proteolipid protein 1; PT - photothrombotic; ROS -reactive oxygen species; SLC17A6/Vglut2 - solute carrier family 17 member 6; S: -signal-to-noise; SSMD - strictly standardized mean difference; SNRIs - serotonin and norepinephrine reuptake Inhibitors; TTC - 2,3,5-triphenyltetrazolium chloride; TEER - transendothelial electrical resistance; TEM - transmission electron microscopy; TRPM2 -transient receptor potential cation channel subfamily M member 2; TBI -traumatic brain injury; ULK1 - unc-51 like autophagy activating ainase 1; V-ATPase - vacuolar-type H-translocating ATPase.
RETREG1/FAM134B-mediated ERGICphagy regulates GSDME-dependent dendritic cell pyroptosis during sepsis.
Duan Y, He PY, Zhu CL … +12 more , Li JR, Chen Y, Zheng LY, Fan Q, Ling H, Wang L, Wu MY, Han ZX, Li T, Yao YM, Dai XG, Yao RQ
Autophagy · 2026 Jun · PMID 41787734 · Full text
During the development of sepsis, aberrant dendritic cell (DC) pyroptosis results in a significant decrease in the numbers of DCs and immune dysfunction. However, the molecular mechanisms regulating DC pyroptosis in seps...
During the development of sepsis, aberrant dendritic cell (DC) pyroptosis results in a significant decrease in the numbers of DCs and immune dysfunction. However, the molecular mechanisms regulating DC pyroptosis in sepsis remain unclear. Emerging evidence indicates that RETREG1/FAM134B (reticulophagy regulator 1) is involved in the regulation of programmed cell death to maintain cell viability. Therefore, this study aimed to investigate the potential role and regulatory pathways of RETREG1 in DC death during sepsis. We found that the upregulation of RETREG1 upon septic challenge was intimately associated with the maintenance of immune function. Depletion of RETREG1 in DC significantly aggravated DC pyroptosis and sepsis-induced immune dysfunction by activating the CASP3 (caspase 3)-GSDME (gasdermin E) signaling pathway. Mechanistically, defective RETREG1 expression inhibited autophagic degradation of the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), resulting in abnormal activation of STING1 (stimulator of interferon response cGAMP interactor 1), which further induced CASP3-GSDME-dependent pyroptosis. Genetic downregulation of prevented the activation of STING1 and GSDME-mediated pyroptosis by disturbing ERGIC structure. These results suggest a novel RETREG1-based protective mechanism against DC-mediated immune impairment during sepsis. Genetic or pharmacological modulation of RETREG1 May represent a promising therapeutic strategy for treating sepsis-induced immune suppression.Abbreviations: 7-AAD: 7-aminoactinomycin D; ANXA5/annexin V: annexin A5; ARF1: ARF GTPase 1; ATP: adenosine triphosphate; CALCOCO1: calcium binding and coiled-coil domain 1; CASP1: caspase 1; cC3: cleaved CASP3; CCDC50: coiled-coil domain containing 50; CD274/PD-L1: CD274 molecule; CFSE: carboxyfluorescein diacetate succinimidyl ester; CGAS: cyclic GMP-AMP synthase; CLP: cecal ligation and puncture; DC: dendritic cell; DEGs: differentially expressed genes; DEPs: differently expressed proteins; ER: endoplasmic reticulum; ERGIC: endoplasmic reticulum-Golgi intermediate compartment; GO: Gene Ontology; GOLGA2/GM130: golgin A2; GSDMD: gasdermin D; GSDME: gasdermin E; GSEA: Gene set enrichment analysis; IFN-I: type I interferon; IKK: IκB kinase; IL2: interleukin 2; IRF3: interferon regulatory factor 3; ITGAX/Cd11c: integrin subunit alpha X; KEGG: Kyoto Encyclopedia of Genes and Genomes; LMAN1/ERGIC53: lectin, mannose binding 1; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; NFKB/NFκB: nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; PBMCs: peripheral blood mononuclear cells; PBS: phosphate-buffered saline; PCD: programmed cell death; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; PRRs: pattern recognition receptors; PYCARD/ASC: PYD and CARD domain containing; RETREG1/FAM134B: reticulophagy regulator 1; SAMHD1: SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1; SEC62: SEC62 preprotein translocation factor; SQSTM1/p62: sequestosome 1; STEEP1: STING1 ER exit protein 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TGFB/TGFβ: transforming growth factor beta; TMED9: transmembrane p24 trafficking protein 9; TLR4: toll like receptor 4; TNF: tumor necrosis factor; T: regulatory T cells; VAP: VAMP associated protein.
Chaperone-mediated autophagy: the Achilles heel of the retinal pigment epithelium during age-related macular degeneration.
Jiménez-Loygorri JI, Cuervo AM, Ferrington DA … +1 more , Boya P
Autophagy · 2026 May · PMID 41778671 · Full text
Chaperone-mediated autophagy (CMA) is a selective autophagy pathway that targets specific proteins containing a KFERQ-like motif for lysosomal degradation. It has been shown by us and others that CMA decreases during phy...
Chaperone-mediated autophagy (CMA) is a selective autophagy pathway that targets specific proteins containing a KFERQ-like motif for lysosomal degradation. It has been shown by us and others that CMA decreases during physiological aging in most tissues, and its impairment is associated with increased incidence of age-related pathologies, such as cardiovascular disease, neurodegenerative disorders or sarcopenia. However, its involvement in age-related macular degeneration (AMD), a prevalent progressive maculopathy that leads to bilateral central vision loss, had not been explored. In the early stages of AMD, the retinal pigment epithelium (RPE), a monolayer of cells that provides trophic support to photoreceptors, already presents major morphological and functional alterations but the cause of this cell type-specific vulnerability is unknown. In our latest work, we analyzed human donor RPE samples and found that CMA is selectively impaired in the RPE of AMD patients compared to healthy donors. These alterations lead to the accumulation of undegraded CMA substrates and untimely recycling of other proteins. Crucially, these findings are conserved in donor-derived iPSC-RPE models. We used this clinically relevant model to assess the consequences of dysfunctional CMA in AMD and found that it caused proteotoxicity, increased oxidative damage, and altered metabolism. Most importantly, using the new-generation CMA activator CA77.1, we restored proteostasis in AMD iPSC-RPE. Our findings shed light on the selective vulnerability of the RPE in AMD and provide evidence in support of CMA as a novel druggable target against AMD.
/ENT1 and /ENT3 differentially regulate autophagy.
Bissa B, Kaur T, Joshi A … +1 more , Govindarajan R
Autophagy · 2026 Jun · PMID 41773325 · Full text
Despite the well-established role of equilibrative nucleoside transporters (ENTs) in salvaging nucleosides for DNA synthesis, the presence of multiple ENT subfamilies within a single genome suggests putative, non-redunda...
Despite the well-established role of equilibrative nucleoside transporters (ENTs) in salvaging nucleosides for DNA synthesis, the presence of multiple ENT subfamilies within a single genome suggests putative, non-redundant functions in maintaining cellular homeostasis. In this study, we demonstrate that, in contrast to endolysosomal /ENT3, which promotes macroautophagy/autophagy, cell surface-localized /ENT1 is capable of inhibiting autophagy by suppressing PRKAA/AMPK phosphorylation. Consistent with this, silencing induces autophagy, whereas silencing suppresses it. Treatment with adenosine (Ado), a shared substrate of and , triggers PRKAA/AMPK phosphorylation and autophagy in a concentration-dependent manner. This effect is PRKAA-dependent, as Ado fails to induce autophagy in -null cells. Mechanistically, elevated expression promotes increased efflux and decreased intracellular retention of Ado, thereby attenuating PRKAA/AMPK activation and autophagic flux. However, this effect is contingent upon the metabolic state of the cells. Importantly, 's regulatory effect is tied to its transport function, as pharmacological inhibition of transport enhances intracellular Ado accumulation, PRKAA/AMPK phosphorylation, and autophagy. Unlike , which modulates the MTOR pathway, does not affect MTOR signaling. Instead, it promotes BECN1-BCL2 interaction, thereby inhibiting autophagosome formation. Notably, autophagy itself differentially regulates and expression, with compensatory upregulation observed when either is modulated. Finally, and mice display autophagic proficiency and deficiency, respectively. These findings underscore a dynamic and reciprocal regulatory relationship between and in autophagy, offering new avenues for therapeutic modulation in autophagy-related disorders.
STING1 exacerbates iodinated contrast-induced acute kidney injury by promoting ferroptosis through chaperone-mediated autophagic degradation of FTH1.
Wu T, Wu X, Cai J … +8 more , Tang CY, Wang XF, Zeng MY, Liu YT, Tang Y, Liu ZW, Meng W, Duan SB
Autophagy · 2026 May · PMID 41766674 · Full text
Iodinated contrast-induced acute kidney injury (CI-AKI) is a common clinical complication with poor prognostic outcomes, yet its molecular mechanisms remain incompletely understood. Ferroptosis, a regulated form of cell...
Iodinated contrast-induced acute kidney injury (CI-AKI) is a common clinical complication with poor prognostic outcomes, yet its molecular mechanisms remain incompletely understood. Ferroptosis, a regulated form of cell death driven by iron overload and lipid peroxidation, has been implicated in CI-AKI. However, its involvement and precise regulation in CI-AKI remain unclear. Here, we identify STING1 (stimulator of interferon response cGAMP interactor 1) as a key mediator of ferroptosis in renal proximal tubular cells (RPTCs). We demonstrate that iodinated contrast media (ICM) activate STING1, triggering ferroptosis. Using proximal tubule-specific knockout mice and primary RPTCs, we show that deficiency mitigates ferroptosis and alleviates CI-AKI. Mechanistically, STING1 interacts with HSPA8/HSC70 (heat shock protein family A (Hsp70) member 8) in patients with acute tubular necrosis and experimental CI-AKI models, facilitating the chaperone-mediated autophagic degradation of FTH1 (ferritin heavy chain 1) and GPX4 (glutathione peroxidase 4). Notably, inhibition of chaperone-mediated autophagy (CMA) via LAMP2A (lysosomal associated membrane protein 2A) knockdown inhibits FTH1 and GPX4 degradation, and attenuates ferroptosis. These findings uncover a novel STING1-driven mechanism linking CMA to ferroptosis in CI-AKI and highlight the STING1 pathway as a potential therapeutic target for contrast-induced renal injury. 3-MA: 3-methyladenine; AIFM2/FSP1: AIF family member 2, ferroptosis suppressor; CLBD: cytoplasmic ligand-binding domain; CGAS: cyclic GMP-AMP synthase; CI-AKI: contrast-induced acute kidney injury; CMA: chaperone-mediated autophagy; CQ: chloroquine; CTT: C-terminal tail; DHE: dihydroethidium; FTH1: ferritin heavy chain 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GPX4: glutathione peroxidase 4; GSH/GSSG: glutathione/glutathione oxidized; KO: knockout; HK-2 cell: human renal proximal tubular epithelial cell; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; IRI: ischemia-reperfusion injury; KFERQ: CMA recognition pentapeptide; LAMP2A: lysosomal associated membrane protein 2A; MDA: malondialdehyde; NCOA4: nuclear receptor coactivator 4; PT: proximal tubule; RPTCs: renal proximal tubule cells; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TMD: transmembrane domain; WT: wild-type.
Control of phagophore membrane expansion: Atg8-Atg1 as the master switch.
Feng YH, Zhu J, Ding Y … +2 more , Yan F, Xie Z
Autophagy · 2026 Jul · PMID 41742660 · Full text
Autophagosome formation is catalyzed by multiple branches of Atg protein machineries, calling for the existence of a master regulator to coordinate their distinct activities. A prime candidate of such a regulator is Atg8...
Autophagosome formation is catalyzed by multiple branches of Atg protein machineries, calling for the existence of a master regulator to coordinate their distinct activities. A prime candidate of such a regulator is Atg8. This protein has a well-established role in controlling phagophore expansion. But the signaling mechanism has been unclear. Our recent work demonstrates that Atg8 recruits activated Atg1 to the phagophore, together forming such a master switch. Our data indicate that different branches of Atg proteins localize to spatially separated zones. The physical distances among the zones, at times exceeding 250 nm, would limit signal transduction efficiency if a signaling molecule were exclusively localized to a single zone. By covering the phagophore surface, Atg8 maintains physical proximity to different Atg machineries, and transmits a permissive signal by recruiting activated Atg1. Compromising Atg8-mediated Atg1 recruitment leads to confinement of Atg1 to the initiation protein condensate and failure of phagophore expansion. Conversely, the Atg8-Atg1 switch can be manually augmented to substantially increase autophagosome size and autophagic flux. Our work thus reveals a critical regulatory circuit of macroautophagy/autophagy that is built on the spatial organization of Atg protein machineries.
Autophagy as a therapeutic linchpin in metabolic diseases and obesity-associated diabetes.
Vakili O, Klionsky DJ, Reiter RJ … +6 more , Ren J, Deshpande A, Ahn KS, Cho WC, Hushmandi K, Kumar AP
Autophagy · 2026 Jul · PMID 41731726 · Full text
Autophagy, a conserved lysosomal degradation pathway, is increasingly recognized as a central regulator of metabolic health. Its impairment contributes directly to obesity and type 2 diabetes by disrupting nutrient sensi...
Autophagy, a conserved lysosomal degradation pathway, is increasingly recognized as a central regulator of metabolic health. Its impairment contributes directly to obesity and type 2 diabetes by disrupting nutrient sensing, stress adaptation, and organelle quality control. Hyperactivation of MTORC1 with insufficient AMPK and SIRT1 signaling suppresses autophagic flux, driving lipid accumulation, insulin resistance, and mitochondrial dysfunction. Clinically relevant consequences include adipose inflammation and hypertrophy, hepatic steatosis with impaired β-oxidation, pancreatic β-cell failure from unresolved ER stress, and skeletal muscle atrophy due to loss of proteostasis. Moreover, defective autophagy across the gut - liver - brain axis exacerbates intestinal barrier dysfunction, endotoxemia, and neuroendocrine imbalance, amplifying systemic metabolic deterioration. Emerging interventions that restore autophagic capacity, including exercise-induced AMPK activation, dietary modulation of unsaturated fatty acids, pharmacological inducers, and nanotechnology-based lysosomal re-acidification show promise in preclinical models. However, the tissue-specific duality of autophagy, where suppression may be beneficial in some contexts but harmful in others, highlights the complexity of therapeutic targeting. This review highlights current mechanistic and translational insights to position autophagy as a therapeutic linchpin in obesity-associated metabolic disease. By aligning molecular pathways with clinical outcomes, we herein highlight opportunities to develop precision strategies that harness autophagy to combat the global burden of obesity and metabolic disorders.: AGEs: advanced glycation endproducts; ALR: autophagic lysosomal reformation; AMPK: AMP-activated protein kinase; AT: adipose tissue; BAT: brown adipose tissue; CMA: chaperone-mediated autophagy; CR: caloric reduction/restriction; DC: diabetic cardiomyopathy; DN: diabetic nephropathy; ER: endoplasmic reticulum; ESCRT: endosomal sorting complexes required for transport; FFAs: free fatty acids; HFD: high-fat diet; HOPS: homotypic fusion and vacuole protein sorting; KO: knockout; LAMs: Lipid-associated macrophages; LD: lipid droplet; MBH: mediobasal hypothalamus; Med diet: Mediterranean diet; MDBs: Mallory-Denk bodies; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; PI3K: phosphoinositide 3-kinase; PtdIns3K-CI: class III phosphatidylinositol 3-kinase complex I; T1D: type 1 diabetes; T2D: type 2 diabetes; TASCC: TOR-autophagy spatial coupling compartment; TRE: time-restricted eating; WAT: white adipose tissue.
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