Autophagy [JOURNAL]
Sun
200 papers
LC3-linked Golgi-bypass exocytosis fortifies epithelial barrier defense.
Wang J, Wang J, Xiao X … +5 more , Zheng L, Lu X, Wang L, Bian X, Lin L
Autophagy · 2026 Jul · PMID 41968658 · Full text
Cells dynamically regulate membrane protein delivery to meet physiological demands, yet how external cues rapidly mobilize unconventional Golgi-bypass exocytic routes remains unclear. Here we define LC3/Atg8-associated...
Cells dynamically regulate membrane protein delivery to meet physiological demands, yet how external cues rapidly mobilize unconventional Golgi-bypass exocytic routes remains unclear. Here we define LC3/Atg8-associated carrier exocytosis (LACES), a conserved program that couples microbial cues to accelerated surface delivery. In the intestine, phenazine-1-carboxamide (PCN) triggers VPS-34-dependent PtdIns3P generation at ILE-1/ERGIC-53 subdomains, enabling Atg8ylation on preexisting single-membrane RAB-8 carriers. This route accelerates delivery of the ABC transporter PGP-1 and improves host survival during infection, while operating independently of the unfolded protein response, canonical macroautophagy/autophagy initiation modules, and LC3-associated phagocytosis regulators. The pathway is engaged by multiple extracellular bacteria and also functions in mammalian epithelia, where PCN increases apical ΔF508-CFTR delivery in polarized Caco-2 cysts with measurable functional improvement and enhances LC3-RAB8 interactions in mouse intestinal epithelium. These findings establish a conserved LC3-linked Golgi-bypass route and illustrate how microbial cues can rapidly rewire epithelial membrane trafficking to fortify barrier defense. ABC: ATP-binding cassette; BFA: brefeldin A; CFTR: CF transmembrane conductance regulator; ERGIC: ER-Golgi intermediate compartment; FRAP: fluorescence recovery after photobleaching; LACES: LC3/Atg8-Associated Carrier Exocytosis; LAP: LC3-associated phagocytosis; PCA: phenazine-1-carboxylic acid; PCN: phenazine-1-carboxamide; PYO: pyocyanin; 1-HP: 1-hydroxyphenazine; ROS: reactive oxygen species; UPR: unfolded protein response.
utilize pyrimidine metabolism to regulate mitophagy for viral replication.
Zhao B, Chen J, Cheng Y … +10 more , Li Y, Zhong L, Chen J, Bi X, Bai J, Dai Q, Ye Y, Zou L, Wang L, Zhou B
Autophagy · 2026 Jul · PMID 41968644 · Full text
DHODH (dihydroorotate dehydrogenase (quinone)) has been demonstrated as a critical regulator of programmed cell death, yet its role in macroautophagy/autophagy remains poorly defined. pose a significant threat to global...
DHODH (dihydroorotate dehydrogenase (quinone)) has been demonstrated as a critical regulator of programmed cell death, yet its role in macroautophagy/autophagy remains poorly defined. pose a significant threat to global public health, and their replication is closely associated with autophagy. Building upon our previous findings that DHODH was a broad-spectrum target for and a key regulator of replication, this study employed RNA-seq screening coupled with functional validation to demonstrate that DHODH affected replication by regulating mitophagy. Notably, we observed remarkable virus genus specificity in this regulatory mechanism. For autophagy-dependent , DHODH deficiency impaired autophagosome-lysosome fusion, thereby suppressing viral replication. Conversely, in autophagy-inhibiting , the blockade of autophagy flux facilitated viral replication. These observations underscore the specificity of DHODH-mediated viral replication regulation. Additionally, compound supplementation assays indicated that DHODH regulated autophagy via pyrimidine nucleotide metabolism, as exogenous pyrimidine precursors restored autophagosome-lysosome fusion. Furthermore, our research uncovered a novel mechanism whereby classical swine fever virus (CSFV) non-structural protein 4A (NS4A) recruited DHODH to mitochondria, facilitating its interaction with MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) through the LC3-interacting region (LIR) domain to activate mitophagy. Collectively, our findings highlight DHODH as a promising antiviral target within the metabolism-autophagy axis, providing novel insights for antiviral drug development.: AMPK: AMP-activated protein kinase; ATF4: activating transcription factor 4; ATG5: autophagy related 5; BafA1: bafilomycin A1; BNIP3L/NIX: BCL2 interacting protein 3 like; BVDV: bovine viral diarrhea virus; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; co-IP: co-immunoprecipitation; COX4: cytochrome c oxidase subunit 4; CQ: chloroquine; CSFV: classical swine fever virus; DAPI: 4',6-diamidino-2-phenylindole; DEGs: differentially expressed genes; DHO: DHODH substrate dihydroorotate; DHODH: dihydroorotate dehydrogenase; DTMUV: duck tembusu virus; FIS1: fission mitochondrial 1; FUNDC1: FUN14 domain containing 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GO: gene ontology; HSPA/HSP70: heat shock protein family A (Hsp70); JEV: Japanese encephalitis virus; KEGG: kyoto encyclopedia of genes and genomes; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mdivi-1: mitochondrial division inhibitor 1; MFF: mitochondrial fission factor; MFN1: mitofusin 1; MFN2: mitofusin 2; MITO: mitochondria; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; MTS: mitochondrial targeting signal; OPTN: optineurin; ORO: DHODH product orotate; PBS: phosphate-buffered saline; PRKN: parkin RBR E3 ubiquitin protein ligase; PYR: pyrazofurin; RAPA: rapamycin; RFP: red fluorescent protein; RNA-seq: RNA sequencing; RT-qPCR: reverse transcription-quantitative real-time polymerase chain reaction; SD: standard deviation; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; UMP: uridine monophosphate; VDAC1: voltage dependent anion channel 1.
A tRNA epitranscriptomic checkpoint coordinates sperm mitochondrial load with embryonic allophagic clearance.
Luo Z, Wan QL, Wu D … +4 more , He C, Rodriguez TA, Zhou Q, Wang H
Autophagy · 2026 Jul · PMID 41968618 · Full text
The strict maternal inheritance of mitochondrial DNA is enforced by the efficient elimination of paternal mitochondria, yet the role of epigenetic regulation in this process remains unclear. In our recent study, we ident...
The strict maternal inheritance of mitochondrial DNA is enforced by the efficient elimination of paternal mitochondria, yet the role of epigenetic regulation in this process remains unclear. In our recent study, we identify the demethylase ALKB‑1 as an essential factor for paternal mitochondrial elimination (PME) in (), functioning through tRNA mA demethylation. ALKB‑1 deficiency leads to tRNA hypermethylation, which disrupts mitochondrial proteostasis and increases ROS production, thereby activating SKN‑1-ATFS‑1 stress signaling. This cascade compromises mitochondrial reduction during spermatogenesis, resulting in an increased burden of paternal mitochondria transmitted to the embryo. Concurrently, ALKB‑1 is required in the embryo to sustain autophagic clearance, evidenced by impaired autophagic flux and delayed PME upon maternal loss. Thus, delayed clearance stems dually from an excessive mitochondrial load in sperm and a compromised autophagic degradation capacity in the embryo. Our work establishes ALKB‑1‑dependent tRNA demethylation as a dual‑germline epitranscriptomic checkpoint that ensures intergenerational mitochondrial quality control.
Coronavirus NSP5 protease cleaves CCDC50 to evade antiviral autophagy.
Li K, Wei H, Yin W … +6 more , Zhou P, Jin H, Jongkaewwattana A, Suolang S, Zhou H, Luo R
Autophagy · 2026 Apr · PMID 41964373 · Publisher ↗
Selective macroautophagy/autophagy is a critical component of innate antiviral defense, relying on selective autophagy receptors to recognize viral cargo and deliver it for lysosomal degradation. In our recent study, we...
Selective macroautophagy/autophagy is a critical component of innate antiviral defense, relying on selective autophagy receptors to recognize viral cargo and deliver it for lysosomal degradation. In our recent study, we demonstrated that porcine deltacoronavirus (PDCoV) evades this pathway through its NSP5 protease. We uncovered a previously unrecognized antiviral function of the selective autophagy receptor CCDC50, which recognizes K63-linked polyubiquitinated PDCoV envelope (E) protein at lysine 72 and mediates its autophagic degradation, thereby restricting viral replication. This antiviral mechanism operates independently of the canonical receptors SQSTM1/p62 and NBR1. We further demonstrate that PDCoV NSP5 cleaves CCDC50 at glutamine 171, a conserved cleavage site also targeted by NSP5 orthologs from porcine epidemic diarrhea virus/PEDV, transmissible gastroenteritis virus/TGEV, and SARS-CoV-2. This cleavage disrupts the interaction of CCDC50 with ubiquitin and MAP1LC3/LC3, thereby impairing autophagic degradation of the E protein. Collectively, these findings establish CCDC50 as a selective autophagy receptor with antiviral activity against coronaviruses and reveal that coronavirus NSP5 promotes infection by proteolytically dismantling receptor-mediated antiviral autophagy.: CCDC50: coiled-coil domain containing 50; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NBR1: NBR1 autophagy cargo receptor; NSP5: nonstructural protein 5; PDCoV: porcine deltacoronavirus; SQSTM1/p62: sequestosome 1.
STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory.
Lin JY, Huang ZB, Fang EF … +1 more , Lu G
Autophagy · 2026 Jun · PMID 41964371 · Full text
PINK1 serves as the central regulator of PINK1-PRKN-mediated mitophagy, and its precise regulation is critical for efficient mitochondrial clearance. Although the cleavage of PINK1 and its subsequent degradation via the...
PINK1 serves as the central regulator of PINK1-PRKN-mediated mitophagy, and its precise regulation is critical for efficient mitochondrial clearance. Although the cleavage of PINK1 and its subsequent degradation via the N-end rule pathway under basal conditions are well understood, how full-length PINK1 stability is regulated following mitochondrial damage has remained elusive. In our recent study, we identified the STUB1-VCP/p97 axis as a mechanism that fine-tunes full-length PINK1 levels during mitophagy. We demonstrate that STUB1 functions as an E3 ubiquitin ligase that catalyzes K48-linked polyubiquitination of full-length PINK1, which is subsequently recognized and extracted by VCP/p97 for proteasomal degradation. Disruption of this axis results in excessive accumulation of full-length PINK1, accelerated turnover of PRKN, and impaired mitophagy. Moreover, we find that this regulatory mechanism is compromised in the brains of patients with Alzheimer disease (AD), and its disruption leads to neuronal mitophagy defects and impaired associated learning capability in . These findings demonstrate that the STUB1-VCP/p97 complex fine-tunes PINK1 levels to ensure efficient mitophagy and preserve mitochondrial homeostasis.: AD, Alzheimer disease; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; MPP, mitochondrial processing peptidase; MQC, mitochondrial quality control; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; SILAC, stable isotope labeling by amino acids in cell culture; STUB1, STIP1 homology and U-box containing protein 1; TPR, tetratricopeptide repeat; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2.
NCOA4-mediated ferritinophagy: emerging role and novel therapeutic target in precision oncology.
Chen D, Jiang X, Duan T … +4 more , Tian Y, Zhang J, Wang X, Tan J
Autophagy · 2026 Apr · PMID 41964368 · Publisher ↗
Iron is vital for life but can be toxic in excess by forming reactive oxygen species. Ferroptosis, a type of regulated cell death, relies on iron-dependent lipid peroxidation and requires a labile iron pool (LIP) in cell...
Iron is vital for life but can be toxic in excess by forming reactive oxygen species. Ferroptosis, a type of regulated cell death, relies on iron-dependent lipid peroxidation and requires a labile iron pool (LIP) in cells. Ferritin stores iron safely, and its degradation increases the LIP. Ferritinophagy, the autophagic breakdown of ferritin, is crucial for releasing stored iron to trigger ferroptosis. This review examines ferritinophagy's molecular mechanisms, highlighting NCOA4 (nuclear receptor coactivator 4) as the main receptor targeting ferritin for lysosomal degradation. It also discusses the regulatory network controlling NCOA4, including transcriptional factors like TP53/p53 and MYC/c-Myc, RNA-binding proteins, and post-translational modifications such as ubiquitination. We explore ferritinophagy-induced ferroptosis as a promising anti-cancer approach. Research shows that various natural compounds, repurposed drugs, and new metal complexes can induce tumor cell death by activating the NCOA4-ferritinophagy pathway, which is crucial for overcoming therapeutic resistance in many cancers. Understanding this pathway highlights the relationship between iron metabolism, macroautophagy/autophagy, and cell death, offering a foundation for new treatments for cancer and iron-related diseases.: FTH1: ferritin heavy chain 1; GPX4: glutathione peroxidase 4; GSH: glutathione; HIF: hypoxia-inducible factor; LIP: labile iron pool; MAPK/JNK: mitogen-activated protein kinase; NCOA4: nuclear receptor coactivator 4; PUFAs: polyunsaturated fatty acids; SLC7A11: solute carrier family 7 member 11; TFRC: transferrin receptor; TFEB: transcription factor EB.
Harnessing chaperone-mediated autophagy for the development of live attenuated influenza vaccines.
Hao J, Si L
Autophagy · 2026 Jun · PMID 41961109 · Full text
Targeted degradation of viral proteins has emerged as a powerful strategy to attenuate virulent viruses into live vaccines. In our recent study, we introduced a lysosome-targeting (LYTAR) live attenuated vaccine platform...
Targeted degradation of viral proteins has emerged as a powerful strategy to attenuate virulent viruses into live vaccines. In our recent study, we introduced a lysosome-targeting (LYTAR) live attenuated vaccine platform that utilizes chaperone-mediated autophagy (CMA), a lysosome-dependent degradation pathway, to conditionally degrade viral proteins and convert virulent influenza A viruses into safe and effective live attenuated vaccines. The LYTAR vaccine approach enables controlled attenuation of viral replication, while preserving the full antigenic composition of the virus and maintaining robust immunogenicity.
Newcastle disease virus exploits Golgi stress and Golgiphagy to promote ferroptosis.
Kan X, Yang M, Xie G … +5 more , Yin Y, Jiang H, Yuan Y, Sun Y, Ding C
Autophagy · 2026 Jun · PMID 41961065 · Full text
Ferroptosis, characterized by iron-dependent lipid peroxidation, has emerged as a pivotal cell death pathway in various diseases, yet its regulation during viral infection remains elusive. Here, we reveal that Newcastle...
Ferroptosis, characterized by iron-dependent lipid peroxidation, has emerged as a pivotal cell death pathway in various diseases, yet its regulation during viral infection remains elusive. Here, we reveal that Newcastle disease virus (NDV) exploits the Golgi apparatus as a central hub to orchestrate ferroptotic cell death in tumor cells. NDV infection provokes robust Golgi stress and Golgiphagy, leading to the selective degradation of ARF1 (ARF GTPase 1), a GA-resident regulator of redox homeostasis, which in turn triggers a cascade of reactive oxygen species accumulation, lipid peroxidation, and ferroptosis. Mechanistically, we show that this process is dependent on the activation of the Golgi stress response and macroautophagy/autophagy-lysosome pathway. Importantly, inhibition of Golgi stress by exogenous spermine not only alleviates NDV-induced ferroptosis, but also demonstrates antiviral and cytoprotective effects, underscoring the translational potential of targeting the Golgi stress axis. Our findings uncover a previously unappreciated axis of virus-host interaction centering on Golgi stress and ferroptosis and suggest that modulation of organelle-specific stress responses represents a promising therapeutic strategy in both antiviral and cancer contexts.: AMPK: AMP-activated protein kinase; ARF1: ARF GTPase 1; ARF4: ARF GTPase 4; ATG7: autophagy related 7; BFA: brefeldin A; CGAS: cyclic GMP-AMP synthase; CHX: cycloheximide; CQ: chloroquine; CREB3: cAMP responsive element binding protein 3; DFO: deferoxamine; ER: endoplasmic reticulum; Fe: ferrous ions, GA: Golgi apparatus; GOLGA2/GM130: golgin A2; GPX4: glutathione peroxidase 4; GSH: glutathione; GSR: Golgi stress response; HCMV: human cytomegalovirus; HSV-1: herpes simplex virus 1; Lip-1: Liproxstatin-1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MDA: malondialdehyde; mtDNA: mitochondrial DNA; MTOR: mechanistic target of rapamycin kinase; NDV: Newcastle disease virus; NCOA4: nuclear receptor coactivator 4; PUFA: polyunsaturated fatty acid; ROS: reactive oxygen species; Rot: rotenone; SLC7A11: solute carrier family 7 member 11; SERPINH1/HSP47: serpin family H member 1; TFE3: transcription factor binding to IGHM enhancer 3; WT: wild-type.
Autophagic extracellular vesicles: a distinct secretory route linking autophagy to extracellular communication.
Wei H, Fu Y
Autophagy · 2026 Jul · PMID 41958120 · Full text
Macroautophagy/autophagy is classically defined as a degradative pathway that delivers cytoplasmic material to lysosomes. However, accumulating evidence indicates that autophagy can also support unconventional secretion....
Macroautophagy/autophagy is classically defined as a degradative pathway that delivers cytoplasmic material to lysosomes. However, accumulating evidence indicates that autophagy can also support unconventional secretion. A recent study identifies a previously unrecognized subtype of small extracellular vesicles termed autophagic extracellular vesicles (AEVs). These vesicles originate from amphisomes formed by the fusion of autophagosomes with multivesicular bodies and are characterized by a size below 100 nm together with the presence of autophagic cargos, ESCRT-III components and RAB13. Importantly, biogenesis of AEVs is distinct from that of classical exosomes, which requires specific components of the ESCRT III complex and the GTPase RAB27A. The further finding that enterovirus can exploit AEVs to infect receptor-negative cells, thereby expanding viral tropism, suggests that secretory autophagy serves as a pivotal mechanism driving pathogen dissemination. This work provides the conceptual framework of extracellular vesicle heterogeneity and positions secretory autophagy as an important contributor to intercellular communication.
architecture of developmentally programmed mitophagy reveals ER-phagophore membrane continuity.
Huang Y, Zheng T, Sun X … +2 more , Wang R, Cai S
Autophagy · 2026 Jul · PMID 41949493 · Full text
Selective mitochondrial clearance by autophagy (mitophagy) is essential for development and cellular homeostasis. However, how phagophores acquire sufficient membrane to engulf large mitochondria remains poorly understoo...
Selective mitochondrial clearance by autophagy (mitophagy) is essential for development and cellular homeostasis. However, how phagophores acquire sufficient membrane to engulf large mitochondria remains poorly understood. Here, we studied the architecture of forming mitophagosomes in the developing intestine by combining cryo-electron tomography (cryo-ET), serialized on-grid lift-in sectioning for tomography (SOLIST), cryo-focused ion beam (cryo-FIB) milling, and volume electron microscopy. Our data reveal that the endoplasmic reticulum (ER) forms continuous membrane connections with the phagophore during mitophagosome formation. In Vps13D mutant enterocytes, stalled mitochondrial phagophore membrane expansion is associated with an accumulation of persistent ER-phagophore membrane continuities. Together, our findings support a model in which the ER can establish direct membrane continuity with the phagophore to facilitate rapid mitophagosome formation. APF: after puparium formation; BLTP: bridge-like lipid transfer protein; CCS: cleaning cross-section; cryo-ET: cryo-electron tomography; cryo-FIB: cryo-focused ion beam; CTF: contrast transfer function; ER: endoplasmic reticulum; HPF: high-pressure freezing; mitolysosome: autolysosome containing a mitochondrion; mitophagophore: mitochondrial phagophore; mitophagy: selective mitochondrial clearance by autophagy; NGS: normal goat serum; OMM: outer mitochondrial membrane; OsO: osmium tetroxide; PB: phosphate buffer; PBSTx: PBS containing 0.3% (w:t) Triton X-100; RCS: regular cross-section; RT: room temperature; RT-FIB-SEM: room-temperature focused ion beam scanning electron microscopy; SOLIST: serialized on-grid lift-in sectioning for tomography; TLD: Through-the-Lens Detector.
SQSTM1/p62-mediated autophagy and antioxidation contribute to white spot syndrome virus pathogenesis in shrimp.
Tungwaravut S, Jaree P, Wang HC … +1 more , Somboonwiwat K
Autophagy · 2026 Jul · PMID 41949469 · Full text
Selective macroautophagy/autophagy, mediated by selective autophagy receptors (SARs), targets cellular cargo and pathogenic proteins for lysosomal degradation. While crucial in antiviral immunity, viruses have evolved st...
Selective macroautophagy/autophagy, mediated by selective autophagy receptors (SARs), targets cellular cargo and pathogenic proteins for lysosomal degradation. While crucial in antiviral immunity, viruses have evolved strategies to evade or exploit selective autophagy. Despite extensive studies in vertebrates, the role of selective autophagy in crustaceans during viral infections remains largely unexplored. This study investigates the molecular mechanism of selective autophagy receptor SQSTM1/p62 (SQSTM1) in the shrimp immune response to white spot syndrome virus (WSSV) infection. We demonstrated that WSSV infection activates SQSTM1-mediated selective autophagy in hemocytes. During infection, SQSTM1 was predominantly localized in the cytoplasm, with partial nuclear localization. silencing reduced viral load and increased shrimp survival by suppressing autophagic activity. SQSTM1 dynamically interacted with the major WSSV envelope protein VP28 during early infection and facilitated WSSV encapsulation within autophagosomes. Apart from selective autophagy, SQSTM1 was involved in antioxidant resistance mechanisms, as shown by its direct binding to KEAP1, an adaptor of the SQSTM1-KEAP1-NFE2L2/Nrf2 pathway. The reduced expression of downstream genes in the SQSTM1-KEAP1-NFE2L2/Nrf2 pathway was observed in -silenced shrimp infected with WSSV, leading to increased HO levels in hemocytes. Together, these findings suggest that SQSTM1-mediated autophagy facilitates viral encapsulation within autophagosomes and regulates the KEAP1-NFE2L2/Nrf2 antioxidant pathway to suppress ROS levels. This mechanism potentially allows the virus to evade the host's immune system and establish a successful infection. This work expands our understanding of host-virus interactions, highlighting the contribution of SQSTM1 to WSSV pathogenesis. AP-MS: affinity purification-mass spectrometry; ATG: autophagy related ; hpi: h post-infection; LIR: LC3-interacting region; SARs: selective autophagy receptors; SQSTM1/p62: sequestosome 1; WSSV: white spot syndrome virus.
Secretory autophagy mediates SLC16A3/MCT4-dependent lactate secretion to drive metastatic progression in triple-negative breast cancer.
Wu SY, Lin HJ, Lan KY … +10 more , Chen HC, Lin CH, Hsu CY, Lee YJ, Chou YY, Chu YS, Chiang WC, Liu HS, Yeh YC, Lan SH
Autophagy · 2026 Jul · PMID 41948828 · Full text
Triple-negative breast cancer (TNBC) exhibits hyperactive EGF (epidermal growth factor) signaling that drives metabolic plasticity and metastasis. Here, we identify secretory macroautophagy/autophagy as a key downstream...
Triple-negative breast cancer (TNBC) exhibits hyperactive EGF (epidermal growth factor) signaling that drives metabolic plasticity and metastasis. Here, we identify secretory macroautophagy/autophagy as a key downstream effector linking EGF signaling to metabolic reprogramming that fuels TNBC metastatic progression. In TNBC cells, EGF stimulation redirected autophagosomes toward the plasma membrane through a SEC22B-dependent route, signifying activation of secretory autophagy. Proteomic profiling of purified autophagosomes revealed enrichment of the lactate transporter SLC16A3/MCT4 and its chaperone BSG/CD147 on autophagosomal membranes. Mechanistically, EGF promoted MAP1LC3/LC3-SLC16A3 interaction, facilitating SLC16A3 trafficking to the plasma membrane and enhancing lactate efflux. Genetic or pharmacological blockade of autophagy abrogated SLC16A3 surface localization, reduced extracellular lactate accumulation, and markedly suppressed lung metastasis originating from orthotopic TNBC tumors in mice. Although pharmacological inhibition of SLC16A3 effectively blocks its transporter activity and reduces lactate secretion, targeting autophagy provides a more precise approach to suppress EGF-driven SLC16A3 expression and the consequent rise in lactate secretion. Clinically, multiplex immunofluorescence of patient tumors demonstrated strong co-expression of EGFR, LC3, and SLC16A3, which correlated with poor disease-free survival. Our study reveals a previously unrecognized EGF-secretory autophagy axis that orchestrates metabolic remodeling in TNBC and highlights the therapeutic potential of targeting the secretory autophagy- SLC16A3-lactate pathway to restrain metastasis.: 3-MA: 3-methyladenine; ATG5: autophagy related 5; ATG7: autophagy related 7; APf: autophagosome fraction; CQ: chloroquine; CRISPR-Cas9: clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; ER: endoplasmic reticulum; ERBB2/HER2: erb-b2 receptor tyrosine kinase 2; GOBP: gene ontology biological process; imBI: induced metabolic bioluminescence imaging; i.p.: intraperitoneal injection; IVIS: in vivo imaging system; LAMP2: lysosomal associated membrane protein 2; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; PLA: proximity ligation assay; PNS: postnuclear supernatant; SEC22B: SEC22 homolog B, vesicle trafficking protein; shRNA: short hairpin RNA; SLC16A3/MCT4: solute carrier family 16 member 3; SNARE: soluble N-ethylmaleimide-sensitive-factor attachment protein receptor; TIRF: total internal reflection fluorescence; TME: tumor microenvironment; TNBC: triple-negative breast cancer; ULK1/Atg1: unc-51 like autophagy activating kinase 1.
Correction.
Autophagy · 2026 Jun · PMID 41937592 · Full text
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Phase separation of C19orf12 regulates BNIP3 protein quality control and maintains neuronal mitophagy.
Shao C, Bhatta S, Kumari M … +6 more , Wu F, Siedlak SL, Torres S, Zhao F, Zhu X, Wang W
Autophagy · 2026 Apr · PMID 41937575 · Publisher ↗
Mutations in , an orphan gene with elusive function, cause mitochondrial membrane protein-associated neurodegeneration (MPAN). Despite the intriguing mitochondrial deficits, the mechanisms underlying the loss of function...
Mutations in , an orphan gene with elusive function, cause mitochondrial membrane protein-associated neurodegeneration (MPAN). Despite the intriguing mitochondrial deficits, the mechanisms underlying the loss of function of C19orf12 in MPAN pathogenesis remain unclear. In this study, we aim to explore the functional impacts of C19orf12 mutations on mitophagy in MPAN models in vitro and in vivo. Our findings suggest that C19orf12 regulates the turnover of mitophagy receptor BNIP3 proteins through the lysosomal degradation pathway. Disruption of this process leads to the accumulation of oxidized BNIP3 proteins on mitochondria that are ineffective in initiating mitophagy. Mechanistically, C19orf12 participates in protein condensate formation by liquid-liquid phase separation to facilitate BNIP3 protein turnover on the mitochondrial membrane. Along with mitophagy deficits, a rodent MPAN model exhibits motor deficits and core pathological features of MPAN, including iron accumulation, axonal spheroids, and neuroinflammation. This study underscores the pivotal role of C19orf12 in regulating the quality control of BNIP3 protein to control mitophagy, highlighting the significance of impaired mitophagy in the pathogenesis of MPAN. ATP: adenosine triphosphate; BafA: bafilomycin A; BNIP3: BCL2 interacting protein 3; BTZ: bortezomib; C19orf12: chromosome 19 open reading frame 12; CFP: cyan fluorescent protein; CHX: cycloheximide; DNP: dinitrophenyl; FCCP: carbonyl cyanide-p-trifluoromethoxyphenylhydrazone; FRAP: fluorescence recovery after photobleaching; GFP: green fluorescent protein; H&E stain: haematoxylin and eosin stain; LCD: low complexity domain; LC/MS: liquid chromatography-mass spectrometry; LLPS: liquid-liquid phase seperation; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mito-SRAI: mitochondrial signal-retaining autophagy indicator; MG132: cbz-leu-leu-leucinal; MMP: mitochondrial membrane potential; MPAN: mitochondrial membrane protein-associated neurodegeneration; NBIA: neurodegeneration with brain iron accumulation;PLA: proximity ligation assay; RFP: red fluorescent protein; ROS: reactive oxygen species; STX17: syntaxin 17; TFAM: transcription factor A, mitochondrial; TOLLES: TOLerance of lysosomal EnvironmentS; YPet: YFP for energy transfer.
African swine fever virus pE199L, as a mitophagy receptor, suppresses antiviral innate immunity to promote viral replication.
Li X, Ren B, Zhang D … +10 more , Dan M, Liu D, Zhang Z, Zhao J, Nan Y, Hiscox JA, Stewart JP, Zhu Z, Zhao Q, Sun Y
Autophagy · 2026 Jul · PMID 41937559 · Full text
The African swine fever virus (ASFV) employs sophisticated strategies to promote viral replication in the host; however, the underlying mechanisms remain incompletely understood. Here, we demonstrated that the ASFV encod...
The African swine fever virus (ASFV) employs sophisticated strategies to promote viral replication in the host; however, the underlying mechanisms remain incompletely understood. Here, we demonstrated that the ASFV encoded pE199L protein acts as a potential mitophagy receptor that disrupted innate immunity through structural mimicry. The pE199L protein localized to mitochondria via its C terminal hydrophobic domain (155-199 aa) and induced mitochondrial fission by promoting DNM1L/Drp1 phosphorylation. Importantly, pE199L contained three LC3-interacting regions (LIRs: W35-I38, F157-L160, F193-L196) that directed autophagic degradation of key immune adaptors. Specifically, pE199L mediated mitophagic clearance of TBK1 (the CGAS-STING1 pathway) and MAVS (the RLR-MAVS pathway), thereby inhibiting type I interferon production and enhancing viral replication. This dual degradation mechanism was confirmed through rescue experiments using autophagy inhibitors and functional assays with LIR mutants. We identifted pE199L as the first canonical mitophagy receptor encoded by ASFV, unveiling a novel immune evasion strategy and a potential target for antiviral vaccine development.: 3-MA: 3-methyladenine; aa: amino acid; ASFV: African swine fever virus; CGAS: cyclic GMP-AMP synthase; co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DNM1L/Drp1: dynamin 1 like; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; hpi: hour post-infection; IFN: interferon; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MOI: multiplicity of infection; MT-CO2/COXII: mitochondrially encoded cytochrome c oxidase II; PINK1: PTEN induced kinase 1; poly(dA:dT): poly(deoxyadenylic-thymidylic) acid; poly(I:C): polyinosinic-polycytidylic acid; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TOMM20: translocase of outer mitochondrial membrane 20; WT: wild-type.
Purifying selection during maternal inheritance of mammalian mtDNA depends on autophagy and bottleneck size.
Papadea P, Larsson NG
Autophagy · 2026 Jun · PMID 41918247 · Full text
Mammalian mitochondrial DNA (mtDNA) is transmitted asexually without recombination and accumulates mutations at a high rate, which eventually should cause a mutational meltdown. Two processes operating in the maternal ge...
Mammalian mitochondrial DNA (mtDNA) is transmitted asexually without recombination and accumulates mutations at a high rate, which eventually should cause a mutational meltdown. Two processes operating in the maternal germline, the genetic bottleneck and purifying selection, are counteracting this decline but the exact molecular mechanisms and their possible link remain incompletely understood. To address this, we investigated the role of autophagy and mtDNA copy number in shaping purifying selection during maternal mtDNA transmission. Using a carefully designed breeding strategy in mice expressing a proofreading-deficient mitochondrial DNA polymerase, we generated animals carrying random mtDNA mutations and simultaneously introduced moderately decreased or increased mtDNA copy number, or impaired autophagy. Mutation patterns in control animals closely resembled those observed in humans, showing strong purifying selection against non-synonymous mutations, particularly in oxidative phosphorylation (OXPHOS) genes. Our recent work provides new insight by identifying autophagy as a key mediator of germline purifying selection of mtDNA. Moreover, we demonstrate that mtDNA copy number directly influences the efficiency of purifying selection, revealing that these two processes are functionally interconnected.
The SNARE protein SYP22 in Arabidopsis interacts with ATG8 to promote the autophagosome-vacuole fusion.
Jung H, Ma W, Kim JH … +3 more , Kwon C, Kang BH, Chung T
Autophagy · 2026 Jul · PMID 41913452 · Full text
In eukaryotic cells, excess or damaged cytoplasmic constituents are targeted into lytic compartments via autophagosomal membrane trafficking. Biogenesis of autophagosomes in fungi, metazoans, and plants relies on the con...
In eukaryotic cells, excess or damaged cytoplasmic constituents are targeted into lytic compartments via autophagosomal membrane trafficking. Biogenesis of autophagosomes in fungi, metazoans, and plants relies on the conserved ATG (autophagy related) proteins. The machinery responsible for autophagosome turnover has been elucidated in yeast and metazoans, but not in plants. Here we examined 14 soluble N-ethylmaleimide-sensitive-factor attachment protein receptors (SNAREs) in by autophagy marker and genetic analyses. We identified SYP22 (Syntaxin of Plants 22) as a SNARE that is necessary for the efficient fusion of autophagosomes with the vacuole. Genetic disruption of led to a reduction in autophagic flux and the accumulation of autophagosomes. The vacuolar Qa-SNARE SYP22 interacted with autophagosomal proteins, such as ATG8 and the R-SNARE VAMP724. Overall, our molecular and genetic analyses of Arabidopsis SNAREs underscore the importance of autophagosome-vacuole fusion in autophagic flux, and provide an insight into how plant vacuolar SNARE proteins recognize the autophagosome and mediate its fusion. As a unique mutant defective in the turnover of autophagosomes, will be useful for overcoming bottlenecks in plant autophagy research.: AIM: Atg8-family interacting motif; ATG: autophagy related; BiFC: bimolecular fluorescence complementation; co-IP: co-immunoprecipitation; ConA: concanamycin A; DMSO: dimethyl sulfoxide; ER: endoplasmic reticulum; HOPS: homotypic fusion and protein sorting; LE: late endosome; PM: plasma membrane; PVC: prevacuolar compartment; SNARE: soluble N-ethylmaleimide-sensitive-factor attachment protein receptor; SYP: Syntaxin of Plants; TEM: transmission electron microscopy; TGN: trans-Golgi network; WT: wild type.
Dual pathways of TFEB activation under lysosomal stress: ATG conjugation-dependent and -independent modes.
Shima T, Nakamura S
Autophagy · 2026 May · PMID 41906739 · Full text
TFEB (transcription factor EB) regulates the expression of autophagy and lysosomal genes, is activated by various cellular stresses, and plays a key role in maintaining cellular homeostasis. Recent work demonstrates that...
TFEB (transcription factor EB) regulates the expression of autophagy and lysosomal genes, is activated by various cellular stresses, and plays a key role in maintaining cellular homeostasis. Recent work demonstrates that TFEB is activated during lysosomal damage through two distinct mechanisms: ATG conjugation-dependent and -independent. TFEB activation proceeds sequentially through two modes. In the early ATG conjugation-independent mode (Mode I), APEX1 interacts with TFEB in the nucleus, maintaining its transcriptional activity and protein stability. In the later ATG conjugation-dependent mode (Mode II), CCT7 and TRIP6 translocate to lysosomes and interact with TFEB, modulating its phosphorylation and nuclear localization. Moreover, TFEB regulation induced by other cellular stresses-such as oxidative stress, proteasome inhibition, mitochondrial damage, and DNA damage-also involves either Mode I or Mode II. Our findings provide new insights into a unified understanding of TFEB regulation under diverse cellular stress conditions.
Correction.
Autophagy · 2026 Mar · PMID 41906734 · Publisher ↗
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Bafetinib enhances anti-tumor immunity by activating the NLRP3 inflammasome in macrophage.
Liu D, Jin X, Zeng Y … +4 more , Zhou X, Wang M, Shen H, Huang Y
Autophagy · 2026 Jul · PMID 41906654 · Full text
Insufficient lymphocyte infiltration in the tumor microenvironment is a major cause of resistance to immunotherapy. Previous studies have indicated that NLRP3 inflammasome activation is crucial for lymphocyte infiltratio...
Insufficient lymphocyte infiltration in the tumor microenvironment is a major cause of resistance to immunotherapy. Previous studies have indicated that NLRP3 inflammasome activation is crucial for lymphocyte infiltration and activation, but safe, effective, and specific NLRP3 inflammasome agonists are still lacking. Here, we identified a clinical phase II drug, bafetinib, that specifically activates the NLRP3 inflammasome through high-throughput drug screening. Bafetinib directly targets and binds to the potassium channel KCNK6/TWIK2, blocking its degradation via the chaperone-mediated autophagy (CMA) pathway to promote potassium efflux, thereby triggering NLRP3 inflammasome activation. Furthermore, we developed a hypoxia-responsive nanoparticle platform capable of targeted delivery of bafetinib (Baf@NPs) to tumors and specific release in the tumor microenvironment. Baf@NPs treatment significantly represses tumor growth and enhances anti-tumor immunity by triggering NLRP3 inflammasome in macrophage. Moreover, the combination of Baf@NPs with PDCD1/PD-1 antibodies further enhanced anti-tumor immunity and improved tumor treatment. Together, our results identify a safe, highly effective and specific NLRP3 inflammasome agonist and underscore it enhances anti-tumor immunity by triggering the NLRP3 inflammasome in macrophages, providing a potential therapeutic strategy for tumor treatment. 3-MA: 3-methyladenine; BMDMs: bone marrow-derived macrophage; CMA: chaperone-mediated autophagy; CHX: cycloheximide; CQ: chloroquine; Co-IP: co-immunoprecipitation; DAPI: 4',6-diamidino-2-phenylindole; TNF/TNF-α: tumor necrosis factor; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; IL1B/IL-1β: interleukin 1 beta; IL6: interleukin 6; KFERQ: lysine-phenylalanine-glutamate-arginine-glutamine; LAMP2A: lysosomal associated membrane protein 2A; LPS: lipopolysaccharide; MG132: carbobenzoxy-L-leucyl-L-leucyl-L-leucinal; NLRP3: NLR family pyrin domain containing 3; siRNAs: small interfering RNAs; WT: wild-type.
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