Autophagy最新文献

{"title":"The ER protein CANX (calnexin)-mediated autophagy protects against alzheimer disease.","authors":"Hongtao Shen, Yuying Xie, Yan Wang, Yusheng Xie, Yongxiang Wang, Zhenyan Su, Laixi Zhao, Shi Yao, Xiaoling Cao, Jinglan Liang, Junrui Long, Rimei Zhong, Jinfeng Tang, Sijie Wang, Liangqing Zhang, Xiaojing Wang, Björn Stork, Lili Cui, Wenxian Wu","doi":"10.1080/15548627.2024.2447206","DOIUrl":"https://doi.org/10.1080/15548627.2024.2447206","url":null,"abstract":"<p><p>Although the relationship between macroautophagy/autophagy and Alzheimer disease (AD) is widely studied, the underlying mechanisms are poorly understood, especially the regulatory role of the initiation signaling of autophagy on AD. Here, we find that the ER transmembrane protein CANX (calnexin) is a novel interaction partner of the autophagy-inducing kinase ULK1 and is required for ULK1 recruitment to the ER under basal or starved conditions. Loss of CANX results in the inactivity of ULK1 kinase and inhibits autophagy flux. In the brains of people with AD and APP-PSEN1 mice, the interaction of CANX and ULK1 declines. In mice, the lack of CANX in hippocampal neurons causes the accumulation of autophagy receptors and neuron damage, which affects the cognitive function of C57BL/6 mice. Conversely, overexpression of CANX in hippocampal neurons enhances autophagy flux and partially contributes to improving cognitive function of APP-PSEN1 mice, but not the CANX variant lacking the interaction domain with ULK1. These findings reveal a novel role of CANX in autophagy activity and cognitive function by cooperating with ULK1.<b>Abbreviation</b>: AD: Alzheimer disease; APEX: ascorbate peroxidase; APP: amyloid beta precursor protein; APP-PSEN1 mice: amyloid beta precursor protein-presenilin 1 transgenic mice; ATG: autophagy related; Aβ: amyloid-β; BiFC: bimolecular fluorescence complementation; CANX: calnexin; EBSS: Earle's balanced salt solution; EM: electron microscopy; IP: immunopurification; KO: knockout; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MWM: Morris water maze; PLA: proximity ligation assay; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; SQSTM1/p62, sequestosome 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":0.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure of the human autophagy factor EPG5 and the molecular basis of its conserved mode of interaction with Atg8-family proteins.","authors":"Yiu Wing Sunny Cheung, Sung-Eun Nam, Gage M J Fairlie, Karlton Scheu, Jennifer M Bui, Hannah R Shariati, Jörg Gsponer, Calvin K Yip","doi":"10.1080/15548627.2024.2447213","DOIUrl":"https://doi.org/10.1080/15548627.2024.2447213","url":null,"abstract":"<p><p>The multi-step macroautophagy/autophagy process ends with the cargo-laden autophagosome fusing with the lysosome to deliver the materials to be degraded. The metazoan-specific autophagy factor EPG5 plays a crucial role in this step by enforcing fusion specificity and preventing mistargeting. How EPG5 exerts its critical function and how its deficiency leads to diverse phenotypes of the rare multi-system disorder Vici syndrome are not fully understood. Here, we report the first structure of human EPG5 (HsEPG5) determined by cryo-EM and AlphaFold2 modeling. Our structure revealed that HsEPG5 is constructed from helical bundles analogous to tethering factors in membrane trafficking pathways but contains a unique protruding thumb domain positioned adjacent to the atypical tandem LIR motifs involved in interaction with the GABARAP subfamily of Atg8-family proteins. Our NMR spectroscopic, molecular dynamics simulations and AlphaFold modeling studies showed that the HsEPG5 tandem LIR motifs only bind the canonical LIR docking site (LDS) on GABARAP without engaging in multivalent interaction. Our co-immunoprecipitation analysis further indicated that full-length HsEPG5-GABARAP interaction is mediated primarily by LIR1. Finally, our biochemical affinity isolation, X-ray crystallographic analysis, affinity measurement, and AlphaFold modeling demonstrated that this mode of binding is observed between <i>Caenorhabditis elegans</i> EPG-5 and its Atg8-family proteins LGG-1 and LGG-2. Collectively our work generated novel insights into the structural properties of EPG5 and how it potentially engages with the autophagosome to confer fusion specificity.<b>ABBREVIATIONS</b>: ATG: autophagy related; CSP: chemical shift perturbation; eGFP: enhanced green fluoresent protein; EM: electron microscopy; EPG5: ectopic P-granules 5 autophagy tethering factor; GST: glutathione S-transferase; HP: hydrophobic pocket; HSQC: heteronuclear single-quantum correlation; ITC: isothermal titration calorimetry; LDS: LC3 docking site; LIR: LC3-interacting region; MD: molecular dynamics; NMR: nuclear magnetic resonance; TEV: tobacco etch virus.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-19"},"PeriodicalIF":0.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PLK2 disrupts autophagic flux to promote SNCA/α-synuclein pathology.","authors":"Chuang Zhang, Zhanpeng Huang, Xinyue Huang, Yanni Ma, Yifan Cao, Zhixiong Zhang, Rui Wang, Haigang Ren, Longtai Zheng, Chun-Feng Liu, Guanghui Wang","doi":"10.1080/15548627.2024.2448914","DOIUrl":"10.1080/15548627.2024.2448914","url":null,"abstract":"<p><p>The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology of Parkinson disease (PD). PLK2 (polo like kinase 2) is an evolutionarily conserved serine/threonine kinase that is more abundant in the brains of all family members, is highly expressed in PD, and is linked to SNCA deposition. However, in addition to its role in phosphorylating SNCA, the role of PLK2 in PD and the mechanisms involved in triggering neurodegeneration remain unclear. Here, we found that PLK2 regulated SNCA pathology independently of S129. Overexpression of PLK2 promoted SNCA preformed fibril (PFF)-induced aggregation of wild-type SNCA and mutant SNCA^S129A. Genetic or pharmacological inhibition of PLK2 attenuated SNCA deposition and neurotoxicity. Mechanistically, PLK2 exacerbated the propagation of SNCA pathology by impeding the clearance of SNCA aggregates by blocking macroautophagic/autophagic flux. We further showed that PLK2 phosphorylated S1098 of DCTN1 (dynactin 1), a protein that controls the movement of organelles, leading to impaired autophagosome-lysosome fusion. Furthermore, genetic suppression of PLK2 alleviated SNCA aggregation and motor dysfunction <i>in vivo</i>. Our findings suggest that PLK2 negatively regulates autophagy, promoting SNCA pathology, suggesting a role for PLK2 in PD.<b>Abbreviation</b>: AD: Alzheimer disease; AMPK: AMP-activated protein kinase; CASP3: caspase 3; DCTN1: dynactin 1; LBs: lewy bodies; LDH: lactate dehydrogenase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP2: microtubule associated protein 2; MTOR: mechanistic target of rapamycin kinase; NH4Cl: ammonium chloride; p-SNCA: phosphorylation of SNCA at S129; PD: Parkinson disease; PFF: preformed fibril; PI: propidium iodide; PLK2: polo like kinase 2; PRKAA/AMPK: protein kinase AMP-activated catalytic subunit alpha; shRNA: short hairpin RNA; SNCA: synuclein, alpha; SQSTM1/p62: sequestosome 1; TH: tyrosine hydroxylase; TX: Triton X-100; ULK1: unc-51 like autophagy activating kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-21"},"PeriodicalIF":0.0,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142960181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nonreceptor tyrosine kinase ABL1 regulates lysosomal acidification by phosphorylating the ATP6V1B2 subunit of the vacuolar-type H⁺-ATPase.","authors":"Caiwei Song, Qincai Dong, Yi Yao, Yan Cui, Chunmei Zhang, Lijun Lin, Lin Zhu, Yong Hu, Hainan Liu, Yanwen Jin, Ping Li, Xuan Liu, Cheng Cao","doi":"10.1080/15548627.2024.2448913","DOIUrl":"10.1080/15548627.2024.2448913","url":null,"abstract":"<p><p>The vacuolar-type H⁺-ATPase (V-ATPase) is a proton pump responsible for controlling the intracellular and extracellular pH of cells. Its activity and assembly are tightly controlled by multiple pathways, of which phosphorylation-mediated regulation is poorly understood. In this report, we show that in response to starvation stimuli, the nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2, a subunit of the V₁ domain of the V-ATPase, and phosphorylates ATP6V1B2 at Y68. Y68 phosphorylation in ATP6V1B2 facilitates the recruitment of the ATP6V1D subunit into the V₁ subcomplex of V-ATPase, therefore potentiating the assembly of the V₁ subcomplex with the membrane-embedded V₀ subcomplex to form the integrated functional V-ATPase. ABL1 inhibition or depletion impairs V-ATPase assembly and lysosomal acidification, resulting in an increased lysosomal pH, a decreased lysosomal hydrolase activity, and consequently, the suppressed degradation of lumenal cargo during macroautophagy/autophagy. Consistently, the efficient removal of damaged mitochondrial residues during mitophagy is also impeded by ABL1 deficiency. Our findings suggest that ABL1 is a crucial autophagy regulator that maintains the adequate lysosomal acidification required for both physiological conditions and stress responses.<b>Abbreviation</b>: ANOVA: analysis of variance; Baf A1: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CRK: CRK proto-oncogene, adaptor protein; CTSD: cathepsin D; DMSO: dimethylsulfoxide; EBSS: Earle's balanced salt solution; FITC: fluorescein isothiocyanate; GFP: green fluorescent protein; GST: glutathione S-transferase; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PD: Parkinson disease; PLA: proximity ligation assay; RFP: red fluorescent protein; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reconsidering the selectivity of bulk autophagy: cargo hitchhiking specifies cargo for degradation.","authors":"Eigo Takeda, Alexander I May, Yoshinori Ohsumi","doi":"10.1080/15548627.2024.2447209","DOIUrl":"10.1080/15548627.2024.2447209","url":null,"abstract":"<p><p>Bulk macroautophagy/autophagy, typically induced by starvation, is generally thought to isolate cytosolic components for degradation in a non-selective manner. Despite the fundamental nature of the eukaryotic degradation pathway, the question of what cargo is isolated by autophagy has remained unaddressed for over 30 years. We recently employed mass spectrometry to analyze the contents of isolated autophagic bodies. In the process of these experiments, we uncovered Hab1 (Highly enriched in Autophagic Bodies 1), a novel protein that is delivered extremely preferentially via autophagy. We report that Hab1 is a novel receptor protein, the N-terminus of which binds Atg8-PE, whereas the C-terminus binds ribosomes. Surprisingly, detailed biochemical and microscopic analyses revealed that ribosome-bound Hab1 is preferentially delivered to the vacuole by \"'hitchhiking'\" on phagophores/isolation membranes that form during bulk autophagy. This is a completely different mechanism of cargo selection that differs from previous descriptions of selective autophagy, in which the cargo-specific receptor proteins initiate phagophore membrane formation via scaffold proteins such as Atg11. We propose that cargo hitchhiking allows for the specification of cargo during bulk autophagy, which is otherwise a non-selective process.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of the mammalian VPS4A as a selective lipophagy receptor.","authors":"Dimitra Dialynaki, Daniel J Klionsky","doi":"10.1080/15548627.2024.2441535","DOIUrl":"10.1080/15548627.2024.2441535","url":null,"abstract":"<p><p>Lipophagy is a selective type of autophagy where lipid droplets are targeted to the lysosome/vacuole for degradation. Even though lipophagy has been reported in various species, many questions remain unaddressed. How are the lipid droplets sequestered to the lysosome? What is the lipophagy receptor? How is this receptor regulated at a posttranslational level? A new collaborative study among several universities conducted on mouse and human hepatocytes sheds light on these questions, deciphering the lipophagy mechanism in the liver. In a recent paper, Das and colleagues identified VPS4A (vacuolar protein sorting 4 homolog A) as a selective receptor, providing new insights into the mechanistic pathway of lipophagy in mammals and its inverse association with steatotic liver diseases.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of N-degron recognin-mediated autophagy by the SARS-CoV-2 PLpro ubiquitin deconjugase.","authors":"Carlos Ayala-Torres, Jiangnan Liu, Nico P Dantuma, Maria G Masucci","doi":"10.1080/15548627.2024.2442849","DOIUrl":"10.1080/15548627.2024.2442849","url":null,"abstract":"<p><p>Viral proteases play critical roles in the host cell and immune remodeling that allows virus production. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) papain-like protease (PLpro) encoded in the large nonstructural protein 3 (Nsp3) also possesses isopeptidase activity with specificity for ubiquitin and ISG15 conjugates. Here, we interrogated the cellular interactome of the SARS-CoV-2 PLpro catalytic domain to gain insight into the putative substrates and cellular functions affected by the viral deubiquitinase. PLpro was detected in protein complexes that control multiple ubiquitin and ubiquitin-like (UbL) regulated signaling and effector pathways. By restricting the analysis to cytosolic and membrane-associated ubiquitin ligases, we found that PLpro interacts with N-recognin ubiquitin ligases and preferentially rescues type I N-degron substrates from proteasomal degradation. PLpro stabilized N-degron carrying HSPA5/BiP/GRP78, which is arginylated in the cytosol upon release from the endoplasmic reticulum (ER) during ER stress, and enhanced the Arg-HSPA5-driven oligomerization of the N-recognin SQSTM1/p62 that serves as a platform for phagophore assembly. However, while in addition to Arg-HSPA5 and SQSTM1/p62, ATG9A, WIPI2, and BECN1/Beclin 1 were detected in PLpro immunoprecipitates, other components of the autophagosome biogenesis machinery, such as the ATG12-ATG5-ATG16L1 complex and MAP1LC3/LC3 were absent, which correlated with proteolytic inactivation of ULK1, impaired production of lipidated LC3-II, and inhibition of reticulophagy. The findings highlight a novel mechanism by which, through the reprogramming of autophagy, the PLpro deubiquitinase may contribute to the remodeling of intracellular membranes in coronavirus-infected cells.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-20"},"PeriodicalIF":0.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival.","authors":"Laura Zein, Marvin Dietrich, Denise Balta, Verian Bader, Christoph Scheuer, Suzanne Zellner, Nadine Weinelt, Julia Vandrey, Muriel C Mari, Christian Behrends, Friederike Zunke, Konstanze F Winklhofer, Sjoerd J L Van Wijk","doi":"10.1080/15548627.2024.2443945","DOIUrl":"10.1080/15548627.2024.2443945","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Lysosomes are the major cellular organelles responsible for nutrient recycling and degradation of cellular material. Maintenance of lysosomal integrity is essential for cellular homeostasis and lysosomal membrane permeabilization (LMP) sensitizes toward cell death. Damaged lysosomes are repaired or degraded via lysophagy, during which glycans, exposed on ruptured lysosomal membranes, are recognized by galectins leading to K48- and K63-linked poly-ubiquitination (poly-Ub) of lysosomal proteins followed by recruitment of the macroautophagic/autophagic machinery and degradation. Linear (M1) poly-Ub, catalyzed by the linear ubiquitin chain assembly complex (LUBAC) E3 ligase and removed by OTULIN (OTU deubiquitinase with linear linkage specificity) exerts important functions in immune signaling and cell survival, but the role of M1 poly-Ub in lysosomal homeostasis remains unexplored. Here, we demonstrate that L-leucyl-leucine methyl ester (LLOMe)-damaged lysosomes accumulate M1 poly-Ub in an OTULIN- and K63 Ub-dependent manner. LMP-induced M1 poly-Ub at damaged lysosomes contributes to lysosome degradation, recruits the NFKB (nuclear factor kappa B) modulator IKBKG/NEMO and locally activates the inhibitor of NFKB kinase (IKK) complex to trigger NFKB activation. Inhibition of lysosomal degradation enhances LMP- and OTULIN-regulated cell death, indicating pro-survival functions of M1 poly-Ub during LMP and potentially lysophagy. Finally, we demonstrate that M1 poly-Ub also occurs at damaged lysosomes in primary mouse neurons and induced pluripotent stem cell-derived primary human dopaminergic neurons. Our results reveal novel functions of M1 poly-Ub during lysosomal homeostasis, LMP and degradation of damaged lysosomes, with important implications for NFKB signaling, inflammation and cell death.&lt;b&gt;Abbreviation&lt;/b&gt;: ATG: autophagy related; BafA1: bafilomycin A&lt;sub&gt;1&lt;/sub&gt;; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CRISPR: clustered regularly interspaced short palindromic repeats; CHUK/IKKA: component of inhibitor of nuclear factor kappa B kinase complex; CUL4A-DDB1-WDFY1: cullin 4A-damage specific DNA binding protein 1-WD repeat and FYVE domain containing 1; DGCs: degradative compartments; DIV: days &lt;i&gt;in vitro&lt;/i&gt;; DUB: deubiquitinase/deubiquitinating enzyme; ELDR: endo-lysosomal damage response; ESCRT: endosomal sorting complex required for transport; FBXO27: F-box protein 27; GBM: glioblastoma multiforme; IKBKB/IKKB: inhibitor of nuclear factor kappa B kinase subunit beta; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; IKK: inhibitor of NFKB kinase; iPSC: induced pluripotent stem cell; KBTBD7: kelch repeat and BTB domain containing 7; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LCD: lysosomal cell death; LGALS: galectin; LMP: lysosomal membrane permeabilization; LLOMe: L-leucyl-leucine methyl ester; LOP: loperamide; LUBAC: linear ubiquitin chain assembly complex; LRSAM1: leucine","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-21"},"PeriodicalIF":0.0,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reticulophagy and viral infection.","authors":"Alexa Wilson, Craig McCormick","doi":"10.1080/15548627.2024.2414424","DOIUrl":"10.1080/15548627.2024.2414424","url":null,"abstract":"&lt;p&gt;&lt;p&gt;All viruses are obligate intracellular parasites that use host machinery to synthesize viral proteins. In infected eukaryotes, viral secreted and transmembrane proteins are synthesized at the endoplasmic reticulum (ER). Many viruses refashion ER membranes into bespoke factories where viral products accumulate while evading host pattern recognition receptors. ER processes are tightly regulated to maintain cellular homeostasis, so viruses must either conform to ER regulatory mechanisms or subvert them to ensure efficient viral replication. Reticulophagy is a catabolic process that directs lysosomal degradation of ER components. There is accumulating evidence that reticulophagy serves as a form of antiviral defense; we call this defense \"xERophagy\" to acknowledge its relationship to xenophagy, the catabolic degradation of microorganisms by macroautophagy/autophagy. In turn, viruses can subvert reticulophagy to suppress host antiviral responses and support efficient viral replication. Here, we review the evidence for functional interplay between viruses and the host reticulophagy machinery.&lt;b&gt;Abbreviations&lt;/b&gt;: AMFR: autocrine motility factor receptor; ARF4: ADP-ribosylation factor 4; ARL6IP1: ADP-ribosylation factor-like 6 interacting protein 1; ATL3: atlastin GTPase 3; ATF4: activating transcription factor 4; ATF6: activating transcription factor 6; BPIFB3: BPI fold containing family B, member 3; CALCOCO1: calcium binding and coiled coil domain 1; CAMK2B: calcium/calmodulin-dependent protein kinase II, beta; CANX: calnexin; CDV: canine distemper virus; CCPG1: cell cycle progression 1; CDK5RAP3/C53: CDK5 regulatory subunit associated protein 3; CIR: cargo-interacting region; CoV: coronavirus; CSNK2/CK2: casein kinase 2; CVB3: coxsackievirus B3; DAPK1: death associated protein kinase 1; DENV: dengue virus; DMV: double-membrane vesicles; EBOV: Ebola virus; EBV: Epstein-Barr Virus; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EMCV: encephalomyocarditis virus; EMV: extracellular microvesicle; ER: endoplasmic reticulum; ERAD: ER-associated degradation; ERN1/IRE1: endoplasmic reticulum to nucleus signalling 1; EV: extracellular vesicle; EV71: enterovirus 71; FIR: RB1CC1/FIP200-interacting region; FMDV: foot-and-mouth disease virus; HCMV: human cytomegalovirus; HCV: hepatitis C virus; HMGB1: high mobility group box 1; HSPA5/BiP: heat shock protein 5; IFN: interferon; IFNG/IFN-γ: interferon gamma; KSHV: Kaposi's sarcoma-associated herpesvirus; LIR: MAP1LC3/LC3-interacting region; LNP: lunapark, ER junction formation factor; MAP1LC3: microtubule-associated protein 1 light chain 3; MAP3K5/ASK1: mitogen-activated protein kinase kinase kinase 5; MAPK/JNK: mitogen-activated protein kinase; MeV: measles virus; MHV: murine hepatitis virus; NS: non-structural; PDIA3: protein disulfide isomerase associated 3; PRR: pattern recognition receptor; PRRSV: porcine reproductive and respiratory syndrome virus; RB1CC1/FIP200: RB1-inducible c","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"3-20"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLC2 (Clathrin Light Chain 2)-ATG8h/ATG8i interactions connect clathrin-mediated endocytosis (CME) and the autophagy pathway.","authors":"Hujiao Lan, Yating Zhao, Minjun Huang, Wenxu Wang, Jianzhong Liu","doi":"10.1080/15548627.2024.2414451","DOIUrl":"10.1080/15548627.2024.2414451","url":null,"abstract":"<p><p>Extensive interconnection has been established between clathrin-mediated endocytosis (CME) and the macroautophagy/autophagy pathway in yeast and mammals. However, the evidence that connects these two pathways in plants has been limited. Starting from the phenotypic similarities in carbon starvation and immune responses shared between the double mutant of CLC2 (clathrin light chain 2) and <i>CLC3</i>, <i>clc2-1 clc3-1</i>, and the <i>atg2-1</i> mutant in Arabidopsis, we found that the autophagy pathway is compromised in the <i>clc2-1 clc3-1</i> mutant. Subsequently, we demonstrated that CLC2 interacts specifically with ATG8h and ATG8i, two clade II ATG8 isoforms. The CLC2-ATG8h/ATG8i interaction depends on an Atg8-family interacting motif (AIM) present in CLC2 and an AIMs docking site (ADS) present in ATG8h, respectively. In addition, CLC2-GFP is subjected to autophagic degradation and the degradation of GFP-ATG8h is significantly reduced in the <i>clc2-1 clc3-1</i> mutant. Last, simultaneously knocking out <i>ATG8h</i> and <i>ATG8i</i> enhances disease resistance, corroborating the functional relevance of the CLC2-ATG8h/8i interactions. These findings reveal that CME and the autophagy pathway are intersected via CLC2-ATG8h/8i interactions in Arabidopsis.<b>Abbreviation</b>: ADS, AIMs docking site; AIM, Atg8-family interacting motif; ATG, autophagy related; CLC, CLATHRIN LIGHT CHAIN; CME, clathrin-mediated endocytosis; RBOHD, RESPIRATORY BURST OXIDASE HOMOLOGUE PROTEIN D; ROS, reactive oxygen species; PM, plasma membrane; SA, salicylic acid.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"246-248"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}