Autophagy [JOURNAL]
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200 papers
Exploiting autophagy-targeting natural compounds for potential antimicrobial actions.
Paik S, Um S, Kim IS … +5 more , Park EJ, Kim KT, Basu J, Oh DC, Jo EK
Autophagy · 2026 Apr · PMID 42047332 · Publisher ↗
Natural products are biologically active compounds used for therapeutic interventions for various diseases, particularly infections. Autophagy is an intracellular catabolic pathway involving lysosomal degradation and is...
Natural products are biologically active compounds used for therapeutic interventions for various diseases, particularly infections. Autophagy is an intracellular catabolic pathway involving lysosomal degradation and is closely associated with immunological pathways, effectively combating bacterial, viral, fungal, and parasitic infections. Accumulating evidence suggests that autophagy activation or inhibition by natural products promotes antimicrobial responses against various pathogens. Numerous natural products can modulate autophagy through diverse signaling pathways, suggesting their potential as a host-directed therapeutic strategy that may complement conventional drug regimens or help mitigate drug resistance in various infectious diseases. However, it remains largely unclear whether these effects are mediated by direct modulation of autophagy or indirectly through associated mechanisms, including enhanced immune defense, attenuation of pathological inflammation, or crosstalk with other organelle functions. Additionally, multiple pathogens can evade host responses; thus, autophagy activation may inadvertently create favorable conditions for certain pathogens. This review discusses the current knowledge of natural products in terms of their antimicrobial actions through autophagy regulation, particularly the roles of distinct natural product classes, such as polyphenols, alkaloids, terpenoids, quinones, peptides, and macrolides in modulating autophagy for potentially contributing to control various infectious diseases. Exploring the intricate molecular interplay between natural products and autophagy in limiting infections may provide valuable insights that could inform the development of innovative host-directed antimicrobial treatments based on autophagy regulation. 3-MA: 3-methyladenine; AM: alveolar macrophages; AMP: antimicrobial peptides; AMPK: 5' adenosine monophosphate-activated protein kinase; ARDS: acute respiratory distress syndrome; ART: artemisinin; ASFV: African swine fever virus; ATG: autophagy related; AZM: azithromycin; BafA1: bafilomycin A; BECN1: beclin 1; BMDM: bone marrow-derived macrophage; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2; CBD: cannabidiol; CF: cystic fibrosis; CGA: chlorogenic acid; CGAS: cyclic GMP-AMP synthase; CHUK/IKKα: component of inhibitor of nuclear factor kappa B kinase complex; CLP: cecal ligation and puncture; CLR: clarithromycin; CMA: chaperone-mediated autophagy; CoV: coronavirus; DHT: dihydrotanshinone I; EGCG: epigallocatechin-3-gallate; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK2: eukaryotic translation initiation factor 2 alpha kinase 2; ESKAPE: , and spp.; ESRRA: estrogen related receptor alpha; FOXO1: forkhead box O1; FUNDC1: FUN14 domain containing 1; HBV: hepatitis B virus; HCV: hepatitis C virus; HDT: host-directed therapy; HIV: human immunodeficiency virus; HMGB1: high mobility group box 1; HSV: herpes simplex virus; IAV: influenza A virus; ICT: isocryptotanshinone; IFN: interferon; IKBKB/IKKβ: inhibitor of nuclear factor kappa B kinase subunit beta; IL: interleukin; INH: isoniazid; IRF3: IFN regulatory factor 3; KEAP1: kelch like ECH associated protein 1; LAMP: lysosomal associated membrane protein; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MDM: monocyte-derived macrophage; MDR: multidrug-resistant; MON: monotropein; Mtb: ; MTOR: mechanistic target of rapamycin kinase; mtROS: mitochondrial ROS; NET: neutrophil extracellular trap; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; NFKB/NF-κB: nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; NLRX1: NLR family member X1; NOTCH1: notch receptor 1; NTM: nontuberculous mycobacteria; OMS: ohmyungsamycin; PAK1: p21 (RAC1) activated kinase 1; PINK1: PTEN induced kinase 1; PKM/PKM2: pyruvate kinase M1/2; PLD: phospholipase D; PM: peritoneal macrophage; PPM1A: protein phosphatase, Mg2+/Mn2+ dependent 1A; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PTEN: phosphatase and tensin homolog; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RELA/p65: RELA proto-oncogene, NF-kB subunit; RIF: rifampicin; ROS: reactive oxygen species; RSV: resveratrol; RUBCN/rubicon: rubicon autophagy regulator; SAR: selective autophagy receptor; SIRT: sirtuin; STING1: stimulator of interferon response cGAMP interactor 1; STX17: syntaxin 17; Tat: trans-activator of transcription; TB: tuberculosis; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TLR: toll like receptor; TNA: tanshinone IIA; TNF: tumor necrosis factor; UA: ursolic acid; ULK1/Atg1: unc-51 like autophagy activating kinase 1; UPR: unfolded protein response; UVRAG: UV radiation resistance associated; VAMP8: vesicle associated membrane protein 8; VDR: vitamin D receptor; WIPI2: WD repeat domain, phosphoinositide interacting 2; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1; ZIKV: Zika virus.
Autophagy reshapes the aging ER.
Donahue EKF, Burkewitz K
Autophagy · 2026 Apr · PMID 42046291 · Publisher ↗
Age-associated changes in organelle structure are often viewed as passive deterioration. Our recent work challenges this view by identifying an evolutionarily conserved, age-onset remodeling of the endoplasmic reticulum...
Age-associated changes in organelle structure are often viewed as passive deterioration. Our recent work challenges this view by identifying an evolutionarily conserved, age-onset remodeling of the endoplasmic reticulum (ER) that is actively driven by ER-phagy. Across multiple cell types and organisms, the ER undergoes a reduction in volume and a shift from rough ER sheets to tubular networks. ER compositional shifts accompany these changes in morphology, with declines of the proteostasis machineries enriched within rough ER and preservation of lipid-associated enzymes tied to tubular subdomains. This remodeling occurs via autolysosomal targeting and degradation of the ER, establishing selective ER-phagy as a conserved aspect of the aging process. Notably, ER-phagy is also engaged by multiple longevity paradigms, resulting in precocious, spatial reorganization of the ER. Furthermore, ER-phagy is required for lifespan extension during mTOR impairment, indicating that ER turnover is adaptive and contributes to longevity. These findings reveal ER-phagy as a regulator of organelle architecture and age-dependent shifts in cell metabolism, thus illuminating important roles for selective autophagy in shaping organelle identity and function across the lifespan.: ER: endoplasmic reticulum; TMEM-131: transmembrane protein 131; UPR: unfolded protein response; IRE-1: inositol-requiring enzyme 1; XBP-1: X-box binding protein 1; mTOR: mechanistic target of rapamycin.
The nuclear receptor ESRRA is a crucial regulator of acute kidney injury through inhibition of the lipophagy-ferroptosis axis.
Yang Y, Zhu X, Fang Y … +10 more , Li J, Shao X, Li S, Jin H, Qi C, Li Z, Gu L, Mou S, Lin Q, Ni Z
Autophagy · 2026 May · PMID 42041131 · Publisher ↗
Acute kidney injury (AKI) is a clinically significant syndrome characterized by a rapid decline in renal function, affecting over 50% of patients in intensive care units. Ferroptosis, a recently identified form of regula...
Acute kidney injury (AKI) is a clinically significant syndrome characterized by a rapid decline in renal function, affecting over 50% of patients in intensive care units. Ferroptosis, a recently identified form of regulated cell death, is driven by iron-dependent lipid peroxidation and has been implicated in AKI pathogenesis. Emerging evidence suggests that lipophagy - a selective autophagic degradation of lipid droplets - potentiates ferroptosis, though the upstream regulatory mechanisms remain poorly understood. ESRRA (estrogen related receptor, alpha), a key transcriptional regulator of fatty acid metabolism and macroautophagy/autophagy, may play a critical role in this process. In this study, we identified ESRRA as a pivotal transcription factor in proximal tubular epithelial cells using single-cell transcriptomic analysis. To investigate its functional role, we employed wild-type mice and tubular epithelial cell-specific deficient mice to establish AKI models. Our findings demonstrated that ESRRA exerted a protective effect by modulating the RAB7-dependent lipophagy-ferroptosis axis. Furthermore, integrating chromatin Immunoprecipitation (ChIP)-seq and JASPAR database analyses, we predicted as a direct transcriptional target of ESRRA. Mechanistically, ESRRA bind to a specific promoter region within , enhancing its expression and subsequently activating the AKT-MTOR signaling pathway, which is required for the suppression of RAB7 mediated lipophagy in renal tubular epithelial cells, thereby attenuating AKI progression. ACSL4: acyl-CoA synthetase long-chain family member 4; AKI: acute kidney injury; AKT/PKB: Akt serine/threonine kinase; ChIP: chromatin Immunoprecipitation; Cis-AKI: cisplatin-induced acute kidney injury; CI-AKI: contrast-induced acute kidney injury; ER: endoplasmic reticulum; ESRRA: estrogen related receptor, alpha; FFAs: free fatty acids; FA-AKI: folic acids-induced acute kidney injury; GPX4: glutathione peroxidase 4; GSH: glutathione; HK-2 cells: human renal proximal tubular epithelial cells; LDs: lipid droplets; LV: lentivirus; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PPARGC1A/PGC1-α: PPARG coactivator 1 alpha; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PLIN2: perilipin 2; PNPLA2/ATGL: patatin-like phospholipase domain containing 2; PT: proximal tubular epithelial cells; PUFA: polyunsaturated fatty acid; RAB7: RAB7, member RAS oncogene family; ROS: reactive oxygen species; SQSTM1: sequestosome 1.
Correction.
Autophagy · 2026 Jul · PMID 42041125 · Full text
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AutoDRY: a genome-wide resource revealing phase-specific control of autophagy activation, amplitude, and termination.
Enserink JM, Chica N
Autophagy · 2026 Apr · PMID 42035279 · Publisher ↗
Despite decades of research identifying the core autophagy-related (ATG) gene products that execute macroautophagy (hereafter autophagy), a systems-level understanding of how the broader genome dynamically tunes this pro...
Despite decades of research identifying the core autophagy-related (ATG) gene products that execute macroautophagy (hereafter autophagy), a systems-level understanding of how the broader genome dynamically tunes this process remains limited. Most studies rely on bulk assays that capture cumulative degradation at a single time point, making it difficult to resolve how autophagy is activated, sustained, and terminated over time. In addition, approaches to quantify temporal response kinetics across thousands of genotypes in parallel at the population level have been lacking, hindering predictive modeling and the development of precise pharmacological strategies to modulate autophagy.
Overexpression of autophagy genes activates lipophagy in Arabidopsis.
Fan J, Kumar Sah S, Xie D … +1 more , Xu C
Autophagy · 2026 May · PMID 42035278 · Publisher ↗
Cells possess an intrinsic recycling system called macroautophagy/autophagy, which delivers obsolete or damaged cytoplasmic components into the vacuole for degradation and reuse. Autophagy-mediated breakdown of organella...
Cells possess an intrinsic recycling system called macroautophagy/autophagy, which delivers obsolete or damaged cytoplasmic components into the vacuole for degradation and reuse. Autophagy-mediated breakdown of organellar membrane lipids supplies fatty acids for the synthesis of triacylglycerols (TAGs), which are then packaged into subcellular organelles called lipid droplets (LDs). Conversely, autophagy contributes to TAG turnover by delivering LDs into vacuoles for breakdown by resident acid lipases. Additionally, LDs can undergo degradation through cytosolic lipolysis mediated by SDP1 (Sugar-Dependent1) lipase in Arabidopsis. Autophagy-mediated LD, a process referred to as lipophagy, has been described in plants. Nevertheless, the precise mechanisms of lipophagy and the specific types of vacuoles involved remain unclear. Here, we show that overexpression of autophagy genes or promotes autophagic activity and significantly reduces LD accumulation. We demonstrate that the decreased LD abundance is not due to increased LD degradation mediated by SDP1 but is dependent on autophagy. The abundance of vacuoles specifically labeled by δ-TIP3 (delta-tonoplast intrinsic protein 3) was markedly decreased in ATG5-overexpressing lines. In addition, disruption of autophagic genes prevented the formation of both δ-TIP3-positive vacuoles and the mysterious vacuolar lumen structures previously termed bulbs, indicating their autophagic origin. Furthermore, confocal imaging analysis revealed close associations between LDs and δ-TIP3-labeled vacuoles, as well as the presence of LDs within vacuoles delimited by δ-TIP3. Together, our findings indicate that overexpression of autophagy genes triggers lipophagy and identify a distinct type of vacuole involved in this process. ATG: autophagy related; AV: autophagic vacuole; ConA: concanamycin A; DsRed: red fluorescent protein; ER: endoplasmic reticulum; GFP: green fluorescent protein; LD: lipid droplet; OLE: oleosin; SDP1: Sugar-Dependent1; TAG: triacylglycerol; TIP: tonoplast intrinsic protein; TLC: thin-layer chromatography.
The 'mitochondrial guardian' α-amyrin links colourful fruit consumption to cognitive resilience.
Cao SQ, Jiménez-Loygorri JI, Boya P … +1 more , Fang EF
Autophagy · 2026 Apr · PMID 42026818 · Publisher ↗
Mitochondrial quality control is essential for maintaining neuronal function and resilience during aging, yet pharmacological strategies that effectively restore mitophagy to maintain mitochondrial homeostasis remain lim...
Mitochondrial quality control is essential for maintaining neuronal function and resilience during aging, yet pharmacological strategies that effectively restore mitophagy to maintain mitochondrial homeostasis remain limited. Emerging evidence suggests that dietary molecules may influence mitochondrial health, although the underlying mechanisms are largely unknown. Here, we summarize our recent finding whereby we have identified a robust mitophagy inducer: α-amyrin (αA). This molecule is a lipid-like pentacyclic triterpenoid abundant in edible plants, such as passion fruit. Mechanistically, αA targets dual leucine zipper kinase (DLK), a neuron-enriched stress kinase that plays a central role in axonal degeneration signaling. Under pathological stress, DLK activates the degeneration mediator SARM1, which can sequester the key autophagy/mitophagy protein ULK1 leading to compromised autophagy (including mitophagy). By specifically binding to DLK, αA releases ULK1 from SARM1-mediated restriction and promotes ULK1-dependent mitophagy, restoring mitochondrial homeostasis. This mechanism reveals the DLK-SARM1-ULK1 cascade as a previously underappreciated regulatory interface linking neuronal stress signaling to mitochondrial surveillance pathways. More broadly, these findings introduce lipid-like dietary molecules as potential "mitochondrial guardians" that preserve organelle integrity through physiological activation of mitophagy. Targeting the DLK-SARM1-ULK1 axis with such molecules may represent a promising strategy for maintaining mitochondrial health and mitigating neurodegenerative processes associated with aging.
Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.
Chaurasia M, Fraiberg M, Subic N … +14 more , Shatz O, Kokabi K, Gogoi O, Trofimyuk O, Tamim-Yecheskel BC, Freud S, Demishtein A, Kopitman E, Goliand I, Chourasia S, Peleg Y, Ainbinder E, Dezorella N, Elazar Z
Autophagy · 2026 Apr · PMID 42023824 · Publisher ↗
HSAN9 is a rare progressive neurodegenerative disease in children linked to bi-allelic loss-of-function mutations in the gene. TECPR2 is a multi-domain protein harboring N-terminal WD repeats and C-terminal TECPR repeat...
HSAN9 is a rare progressive neurodegenerative disease in children linked to bi-allelic loss-of-function mutations in the gene. TECPR2 is a multi-domain protein harboring N-terminal WD repeats and C-terminal TECPR repeats, followed by a functional LIR motif that serves in phagophore targeting. Here, we demonstrate that the absence of TECPR2 results in impaired mitophagy, which can be restored by expressing its C-terminal domain. Accordingly, we uncover severe mitochondrial dysfunction and accumulation of mitochondrial content in primary fibroblasts derived from an HSAN9 patient, as well as in embryonic fibroblasts and dorsal root ganglia derived from an HSAN9 mouse model. Notably, these mitochondrial defects are mediated by mitochondrial stress through the activation of the integrated stress response (ISR), whereas mitochondrial function is restored by pharmaceutical or genetic suppression of ISR. Our findings establish a new connection between mitophagy and ISR in maintaining mitochondrial homeostasis during neurodegeneration.: Baf. A: bafilomycin A; CYCS: cytochrome c, somatic; HSAN9: hereditary sensory and autonomic neuropathy IX; ISR: integrated stress response; OA: oligomycin + antimycin A; ROS: reactive oxygen species; TECPR2: tectonin beta-propeller repeat containing 2.
A CRISPR-Cas9 screen identifies LAPTM4A (lysosomal protein transmembrane 4 alpha) as a key host barrier against PRRSV infection.
He Z, Liu M, Zhang N … +4 more , Yan J, Li F, Zhao P, Guo C
Autophagy · 2026 May · PMID 42020342 · Publisher ↗
Porcine reproductive and respiratory syndrome virus (PRRSV) manipulates host intracellular processes, particularly macroautophagy/autophagy and lysosomal function, to facilitate its replication and spread. However, the p...
Porcine reproductive and respiratory syndrome virus (PRRSV) manipulates host intracellular processes, particularly macroautophagy/autophagy and lysosomal function, to facilitate its replication and spread. However, the precise host factors and molecular mechanisms by which PRRSV remodels the autophagy-lysosome axis remain poorly defined. Here, we performed a CRISPR-Cas9 knockout screen targeting 1,332 genes involved in protein degradation, metabolism, and vesicular trafficking, and identified LAPTM4A (lysosomal protein transmembrane 4 alpha) as a critical antiviral factor involved in the lysosomal pathway. A yeast two-hybrid screen identified LAPTM4A as an interactor of PRRSV GP5 (glycoprotein 5). Mechanistically, GP5 recruits the E3 ubiquitin ligase NEDD4 and the autophagy receptor SQSTM1/p62 to promote K63-linked polyubiquitination of LAPTM4A, leading to its autophagic degradation. This selective degradation activates the AMPK-ULK1-MAP1LC3/LC3 signaling cascade, initiating autophagy while facilitating MTOR-lysosome colocalization, thereby suppressing TFEB nuclear translocation and transcription of lysosome-related genes. The resulting incomplete autophagic flux enhances viral replication. Additionally, in terms of host defense, LAPTM4A maintains lysosomal homeostasis by restraining excessive autophagy through AMPK-ULK1-LC3 signaling and promoting TFEB-dependent lysosomal gene expression by impairing the binding of RPTOR/raptor to MTOR, thus providing broad antiviral protection against multiple RNA viruses. Collectively, our findings identify LAPTM4A as a central regulator of lysosome-autophagy homeostasis and reveal a viral strategy that dismantles this defense axis to facilitate infection.: ATG5: autophagy related 5; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; Baf A1: bafilomycin A; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DMVT library: protein degradation, metabolism, and vesicular trafficking library; LAPTM4A: lysosomal protein transmembrane 4 alpha; MAGeCK: model-based analysis of genome-wide CRISPR-Cas9 knockout; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NC: negative control; PAMs: porcine alveolar macrophages; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PRRSV: porcine reproductive and respiratory syndrome virus; qRT-PCR: quantitative real-time PCR; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TCID: 50% tissue culture infective dose; TFEB: transcription factor EB; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type.
Getting a handle on RAB1: from Golgi trafficking to mitophagy.
van Vliet AR
Autophagy · 2026 Jul · PMID 42015342 · Full text
The small GTPase RAB1 is essential for life. A knockout of RAB1 is not only embryonically lethal, but even triggers cell death in a cultured cell line, underscoring its importance for cellular homeostasis. Previous work...
The small GTPase RAB1 is essential for life. A knockout of RAB1 is not only embryonically lethal, but even triggers cell death in a cultured cell line, underscoring its importance for cellular homeostasis. Previous work has shown that RAB1 plays a key role in protein and membrane trafficking as a player in the ER-to-Golgi trafficking pathway. Here, RAB1 has been shown to interact with COPII vesicles that have left the ER and are arriving at the Golgi. In addition, RAB1 is an essential part of autophagy initiation, where loss of RAB1 leads to defects very early in the pathway. To complicate matters further, there is a non-trivial overlap in phenotype between a Golgi trafficking defect and an autophagy initiation problem, as ATG9A vesicle trafficking and the general importance of the Golgi in autophagy illustrates. Given these hurdles, how would one get a handle on the molecular mechanism of RAB1? In this Punctum, I discuss our recent mapping of a new RAB1 interactome that provides fresh insights into its multifaceted functions.
Enhanced autophagy drives endothelial tight junction loss, BBB disruption, and behavioral deficits during inflammation.
Peng M, Chen W, Gao Q … +6 more , Zhu X, Yu L, Zhang L, Zou X, Hu Z, Zhang L
Autophagy · 2026 Apr · PMID 42003242 · Publisher ↗
The blood-brain barrier (BBB) protects the brain but becomes compromised during systemic inflammatory conditions such as sepsis. The mechanisms driving BBB disruption remain incompletely understood. Here, we identified a...
The blood-brain barrier (BBB) protects the brain but becomes compromised during systemic inflammatory conditions such as sepsis. The mechanisms driving BBB disruption remain incompletely understood. Here, we identified a significant enrichment of the macroautophagy/autophagy-lysosome-related pathway in the upregulated proteome using quantitative proteomics on brain microvessels from mice after cecal ligation and puncture (CLP) that induces polymicrobial sepsis. CLP progressively induced autophagic flux in brain endothelial cells, peaking at 24 h post-procedure before subsiding. Similarly, an mRFP-GFP-LC3 reporter assay and immunoblotting showed that lipopolysaccharide (LPS) treatment increased autophagic flux in bEnd.3 cells in a time- and dose-dependent manner. Mice intraperitoneally (IP) injected with the autophagy inhibitors chloroquine (CQ) or 3-methyladenine (3-MA) were resistant to BBB disruption caused by CLP or IP injection of LPS, whereas those injected with the autophagy inducer rapamycin (Rapa) were more susceptible. CQ and 3-MA reduced, while Rapa increased, CLP-induced lethality in mice. These effects were confirmed using a dextran infiltration assay on bEnd.3 cell transwell cultures. CQ alleviated both the acute disruption of the tight junction proteins TJP1/ZO-1 and CLDN5 in brain microvessels and the long-term memory and anxiety deficits in LPS-challenged mice. siRNA-mediated knockdown of the SNARE protein STX17, which inhibits autophagosome-lysosome fusion, attenuated LPS-induced tight junction protein degradation in bEnd.3 cells. Importantly, inhibition of TLR4 or its downstream kinase TBK1 reduced LPS-induced autophagy and preserved tight junction proteins, implicating TLR4-TBK1 signaling in endothelial autophagy activation. These results suggest that excessive autophagy in endothelial cells drives BBB damage and cognitive dysfunction in sepsis.: 3-MA: 3-methyladenine; ATG5: autophagy related 5; BBB: blood-brain barrier; bEnd.3 cells: brain-derived endothelial cells.3; CLP: cecal ligation and puncture; CQ: chloroquine; EPM, elevated plus maze; GO: Gene Ontology; IP: intraperitoneal; LPS: lipopolysaccharide; MAP1LC3/LC3-II: microtubule associated protein 1 light chain 3-II; MWM: Morris Water Maze; NOR: novel object recognition test; OFT: open field test; Rapa: rapamycin; SAE: sepsis-associated encephalopathy; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; TBK1: TANK binding kinase 1; TICAM1/TRIF: TIR domain containing adaptor molecule 1; TLR4: toll like receptor 4; TMT: tandem mass tag.
The pleiotropic impact of chaperone-mediated autophagy on skeletal muscle integrity.
Dialynaki D, Klionsky DJ
Autophagy · 2026 May · PMID 42003010 · Full text
Skeletal muscle is a fundamental tissue as it is found throughout the body, sustains posture, and produces movement. Yet, skeletal muscle disorders, such as myopathies, affect a large percentage of the population, degrad...
Skeletal muscle is a fundamental tissue as it is found throughout the body, sustains posture, and produces movement. Yet, skeletal muscle disorders, such as myopathies, affect a large percentage of the population, degrading an individual's quality of life. A recent study links myopathy progression to the decline in chaperone-mediated autophagy that occurs during aging. Underscoring the importance of a balanced CMA pathway in maintaining skeletal muscle function and integrity, the study also provides mechanistic insights into the pathways that are dysregulated due to defective CMA and presents an approach to reverse the age-dependent decline in this process.: ATP2A1, ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1; CMA, chaperone-mediated autophagy; HSPA8, heat shock protein family A (Hsp70) member 8; LAMP2A, lysosomal associated membrane protein 2A.
PBK-Loaded secretory autophagosomes drive radiotherapy-induced systemic adipose depletion via MAPK/ERK-PRKA/PKA-LIPE/HSL signaling: a therapeutic target for esophageal cancer cachexia.
Li Z, Jia Y, Chen X … +6 more , Li G, Li Z, Wang H, Yang T, Chen A, Wang J
Autophagy · 2026 Apr · PMID 41988986 · Publisher ↗
Radiotherapy, while a cornerstone treatment for esophageal squamous cell carcinoma (ESCC), is paradoxically associated with significant weight loss that portends poor patient outcomes. The mechanisms driving this metabol...
Radiotherapy, while a cornerstone treatment for esophageal squamous cell carcinoma (ESCC), is paradoxically associated with significant weight loss that portends poor patient outcomes. The mechanisms driving this metabolic complication remain elusive. Here, we identified adipose depletion - rather than muscle atrophy - as the primary contributor to radiotherapy-induced weight loss in ESCC. We demonstrated that secretory autophagosomes (SAPs) released post-irradiation mediate systemic fat loss through integrated and studies. Proteomic profiling revealed enrichment of PBK (PDZ binding kinase) in radiation-induced SAPs, with functional studies establishing PBK as the master regulator of adipocyte lipolysis. Mechanistically, SAP-delivered PBK activated MAPK1/ERK2 (mitogen-activated protein kinase 1), triggering a downstream PRKA/PKA-LIPE/HSL signaling cascade that increases lipolytic rate. Clinically, elevated circulating SAPs levels predicted severe fat loss and reduced median survival in a ESCC cohort. Critically, pharmacological inhibition of PBK with OTS-514 rescued adipose mass in preclinical models while enhancing tumor radiosensitivity. Our work redefines radiotherapy-induced cachexia as an adipose-centric process orchestrated by SAPs, unveils PBK as a therapeutic target, and provides actionable biomarkers for early intervention. These findings bridge the gap between localized radiotherapy and systemic metabolic sequelae, offering a dual-strategy approach to improve both survival and quality of life in ESCC patients. ADSCs: adipose-derived stem cells; CM: conditioned media; ESCC: esophageal squamous cell carcinoma; EVs: extracellular vesicles; eWAT: epididymal white adipose tissue; GA: gastrocnemius muscle; iWAT: inguinal white adipose tissue; LIPE/HSL: lipase E, hormone sensitive type; LIR: LC3-interacting region; MAP2K1/MEK1: mitogen-activated protein kinase kinase 1; MAPK/ERK: mitogen-activated protein kinase; OS: overall survival; PBK: PDZ binding kinase; PRKA/PKA: protein kinase cAMP-dependent; RT: radiotherapy; SAPs: secretory autophagosomes; sEVs: small extracellular vesicles.
Trophoblast aging driven by IL33 deficiency elevates recurrent pregnancy loss risk through SNAP29 lactylation-mediated autophagy impairment.
Lu JJ, Sheng YR, Hu WT … +4 more , Liu YK, Xie F, Li MQ, Zhu XY
Autophagy · 2026 Jul · PMID 41975562 · Full text
Emerging evidence implicates premature placental senescence as a central driver of pregnancy complications, though its underlying mechanisms remain elusive. Here, we report marked downregulation of IL33 (interleukin 33)...
Emerging evidence implicates premature placental senescence as a central driver of pregnancy complications, though its underlying mechanisms remain elusive. Here, we report marked downregulation of IL33 (interleukin 33) in villi from unexplained recurrent pregnancy loss (URPL) patients, concomitant with elevated trophoblast senescence. More importantly, knockout mice exhibited placental senescence and impaired trophoblast invasion. Mechanistically, senescent trophoblasts displayed metabolic dysregulation - including enhanced glycolysis and lactate accumulation - which disrupted macroautophagic/autophagic flux and mitochondrial function. Lactate-induced lysine lactylation at residue K169 of SNAP29 (synaptosome associated protein 29) promoted its degradation, impairing macroautophagy/autophagy and trophoblast function, ultimately driving pregnancy loss. In interventional studies, senotherapies with metformin or dasatinib plus quercetin restored placental development and improved pregnancy outcomes in both IL33-deficient and inflammation-induced miscarriage models. Our findings establish the IL33-senescence-lactate axis as a critical pathway in URPL pathogenesis and support senomodulation as a therapeutic strategy.: 2-DG: 2-deoxy-D-glucose; BafA1: bafilomycin A1; CHX: cycloheximide; CTB: cytotrophoblasts; D-gal: D-galactose; EVT: extravillous trophoblasts; HDAC: histone deacetylase; H2O2: hydrogen peroxide; IL33: Interleukin 33; LPS: lipopolysaccharide; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; SNAP29: synaptosome associated protein 29; STB: syncytiotrophoblasts; UMAP: uniform manifold approximation and projection; URPL: unexplained recurrent pregnancy loss; VP: etoposide.
Unravelling chaperone-mediated microautophagy targeting KFERQ-like motif containing proteins in yeast.
Upadhayay K, Bhardwaj P, Farooqi N … +5 more , Rabha B, Mishra A, Verma K, Singh R, Sharma D
Autophagy · 2026 Jul · PMID 41968850 · Full text
Under prolonged starvation, mammalian cells activate chaperone-mediated autophagy (CMA) that degrades cellular proteins containing KFERQ-like motifs via lysosomes. During CMA, the lysosomal membrane protein LAMP2A acts a...
Under prolonged starvation, mammalian cells activate chaperone-mediated autophagy (CMA) that degrades cellular proteins containing KFERQ-like motifs via lysosomes. During CMA, the lysosomal membrane protein LAMP2A acts as an essential receptor for the HSPA8/HSC70-CMA substrate complex. Thus, the evidence of CMA in organisms lacking LAMP2A on lysosomes/vacuoles is still lacking. Here, we examined the fate of proteins containing such motifs in that lack the CMA receptor on vacuoles. Intriguingly, we found that even in the absence of LAMP2A, proteins containing such motifs translocate into vacuoles upon prolonged starvation. We report for the first time that phosphatidylserine acts as an Hsp70-family protein-substrate receptor on the vacuolar membrane to facilitate the substrate translocation into vacuoles. As the newly discovered degradation pathway is dependent upon cytosolic Hsp70 (as in CMA) as well as the ESCRT complex, and involves invagination of the vacuolar membrane, we refer to it as chaperone-mediated microautophagy. Taken together, this study has led to the identification of a novel cellular pathway in that facilitates the clearance of cellular proteins under chronic stress.: CMA: chaperone-mediated autophagy; CMA-tag: KFERQ motif; ESCRT: endosomal sorting complexes required for transport; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HSPA8: heat shock protein 8; LAMP2A: lysosomal-associated membrane protein type 2A; Lact-C2: lactadherin C2 domain; PAmCherry: photoactivatable mCherry; PBS: phosphate-buffered saline; PS: phosphatidylserine; PtdIns4P: phosphatidylinositol-4-phosphate; RFP: red fluorescent protein; TBST: Tris-buffered saline with Tween 20.
Discovery of a novel TFEB activator targeting lysosomal dysfunction in amyotrophic lateral sclerosis using artificial intelligence-based virtual screening.
Li A, Xiao X, Qin D … +1 more , Su H
Autophagy · 2026 Apr · PMID 41968679 · Publisher ↗
Lysosomal dysfunction is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), yet effective pharmacological strategies to restore lysosomal homeostasis remain limited....
Lysosomal dysfunction is a defining feature of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), yet effective pharmacological strategies to restore lysosomal homeostasis remain limited. Transcription factor EB (TFEB), a master transcriptional regulator of lysosomal biogenesis, has emerged as an attractive therapeutic target. In our recent study published in , we established a robust artificial intelligence (AI) - driven virtual screening pipeline and identified isoginkgetin (ISO) as a potent TFEB activator that effectively promotes lysosomal biogenesis and enhances lysosomal function. Importantly, ISO exhibits potent neuroprotective effects against motor neuron degeneration in ALS models. Using this AI-driven strategy, we identified a previously unrecognized neuroprotective mechanism by which ISO protects motor neurons through TFEB-dependent restoration of lysosomal function, validating lysosomal function as a promising therapeutic target for ALS. Collectively, this work establishes that AI-powered screening to identify mTORC1-independent TFEB agonists is a valuable paradigm for the discovery and development of therapeutic agents against ALS and other neurodegenerative diseases.
TAX1BP1 targets STING1 via microautophagy and Golgiphagy to limit inflammatory signaling.
Suklabaidya S, Mohanty S, Harhaj EW
Autophagy · 2026 Jul · PMID 41968678 · Full text
The CGAS-STING1 pathway plays a key role in detecting cytosolic DNA and initiating immune responses. Excessive STING1 activation can lead to aberrant inflammation and autoinflammatory diseases; therefore, the STING1 degr...
The CGAS-STING1 pathway plays a key role in detecting cytosolic DNA and initiating immune responses. Excessive STING1 activation can lead to aberrant inflammation and autoinflammatory diseases; therefore, the STING1 degradation pathway is tightly regulated by several negative regulatory mechanisms. In our recent study, we show that the selective autophagy receptor TAX1BP1 functions as a negative regulator of STING1 signaling. TAX1BP1 promotes the degradation of activated STING1 through microautophagy by facilitating the interaction of STING1 with the ESCRT-0 protein HGS, and selective autophagy of the Golgi apparatus in a process known as Golgiphagy. In TAX1BP1-deficient macrophages, STING1 aggregates accumulate at the trans-Golgi network, leading to stronger antiviral and inflammatory responses. These findings support a novel mechanism linking organelle quality control and innate immune regulation, highlighting Golgiphagy as an important feedback mechanism that limits STING1 signaling.: cGAMP: cyclic guanosine monophosphate-adenosine monophosphate; CGAS: Cyclic GMP-AMP synthase; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; ECTV: ectromelia virus; HGS: hepatocyte growth factor-regulated tyrosine kinase substrate; IKK: IκB kinase; IRF3: interferon regulatory factor 3; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TAX1BP1: Tax1 binding protein 1.
Mitochondria power the cell's recycling center.
Tian Z, Guan JL, Diao J
Autophagy · 2026 Jul · PMID 41968674 · Full text
The lysosome has long been understood as an organelle defined by its acidity. The steep proton gradient maintained within its lumen, a pH of 4.5 to 5.0, is prerequisite for the activation of resident hydrolases and, by e...
The lysosome has long been understood as an organelle defined by its acidity. The steep proton gradient maintained within its lumen, a pH of 4.5 to 5.0, is prerequisite for the activation of resident hydrolases and, by extension, for all lysosome-dependent degradation, including autophagy. This acidic luminal pH is maintained by the V-type ATPase (V-ATPase), which hydrolyzes ATP to actively pump protons into the lumen. Yet a fundamental question has lingered: where do all these protons ultimately come from? Most recently, we found a striking answer - the mitochondrion.
CORO1C (coronin 1C) promotes autophagosome formation by coordinating branched actin network dynamics.
Zhang G, Yu N, Sun Y … +4 more , Li X, Sun L, Liu G, Huang Y
Autophagy · 2026 Jul · PMID 41968673 · Full text
Macroautophagy/autophagy is a critical cellular process that maintains the cellular homeostasis by degrading and recycling cytotoxic material. Despite its importance, the intricate mechanisms governing this process remai...
Macroautophagy/autophagy is a critical cellular process that maintains the cellular homeostasis by degrading and recycling cytotoxic material. Despite its importance, the intricate mechanisms governing this process remain partially elusive. Here, we designed and performed a genome-wide loss-of-function screen on a mouse haploid ESC mutant library and identified the actin-binding protein CORO1C (coronin 1C) as a previously unrecognized regulator of mammalian autophagy. Interactions between CORO1C and the ACTR2/ARP2 (actin related protein 2)-ACTR3/ARP3 complex are essential for branched actin network assembly, SQSTM1/p62 body formation, and maintaining autophagosome structural integrity. Unlike CORO1A and CORO1B, CORO1C possesses a unique second actin-binding site involved in regulating the branched actin network and autophagic process. Notably, newborn mice died earlier in starvation than wild-type littermates and multiple tissues showed autophagy-deficient phenotypes. Moreover, the adult -deficient mice exhibit severe spatial learning memory impairment. Collectively, our research uncovered the surprising role of CORO1C in promoting the formation of branched actin network and its central role in the assembly of structures vital to autophagy.: ACTR2/ARP2: actin related protein 2; ACTR3/ARP3: actin related protein 3; ARPC2: actin related protein 2/3 complex, subunit 2; ATG: autophagy related; ATG5: autophagy related 5; BafA1: bafilomycin A; CQ: chloroquine; FACS: fluorescence-activated cell sorting; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; haESC: haploid embryonic stem cell; HML: haploid-mutant library; IF: immunofluorescence; KO: knockout; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3B; RB1CC1/FIP200: RB1-inducible coiled-coil 1; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TEM: transmission electron microscopy; WB: western blotting; WT: wild type.
EXOC5/SEC10 attenuates antiviral IFN-I signaling by targeting STING1 for autophagic degradation.
Ma W, Xu Y, Yu J … +7 more , Sun F, Yu X, He L, Li Y, He DC, Wang H, He H
Autophagy · 2026 Jul · PMID 41968661 · Full text
EXOC5/SEC10, the central subunit of the exocyst complex, is crucial for the trafficking of secretory vesicles to the plasma membrane. However, its role in innate immunity and viral replication remains unclear. Here we de...
EXOC5/SEC10, the central subunit of the exocyst complex, is crucial for the trafficking of secretory vesicles to the plasma membrane. However, its role in innate immunity and viral replication remains unclear. Here we demonstrate that EXOC5 acts as a negative regulator of DNA virus-triggered CGAS-STING1 signaling via targeting STING1. Mechanistically, EXOC5 facilitates the autophagic degradation of STING1 via K63-linked polyubiquitination at Lys224 and Lys338 by the E3 ligase TRIM56, which serves as a recognition signal for the cargo receptor SQSTM1/p62 (sequestosome 1). Furthermore, EXOC5 inhibits antiviral innate immunity and promotes viral replication via EXOC5-TRIM56-STING1-SQSTM1 signal transduction. More importantly, myeloid-specific deletion of in mice improves survival and reduces viral load. In general, these findings revealed a negative feedback loop of type I interferon signaling through the EXOC5-TRIM56-STING1-SQSTM1 axis, which has the potential to serve as a new target for the development of antiviral therapeutics that regulate the host immune response. BafA1: bafilomycin A1; BMDMs: bone marrow-derived macrophages; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; EXOC5/SEC10: exocyst complex component 5; HAdV-4: human adenovirus type 4; HSV-1: herpes simplex virus type 1; HT-DNA: herring testis deoxyribonucleic acid; IFN: interferon; IRF3: interferon regulatory factor 3; ISD: interferon stimulatory DNA; PMs: peritoneal macrophages; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TBK1: TANK binding kinase 1; VACV70: 70-mers of dsDNA representing the genome of vaccinia virus.
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