Autophagy最新文献

{"title":"Bunyavirus SFTSV nucleoprotein exploits TUFM-mediated mitophagy to impair antiviral innate immunity.","authors":"Wen-Kang Zhang, Jia-Min Yan, Min Chu, Bang Li, Xiao-Lan Gu, Ze-Zheng Jiang, Ze-Min Li, Pan-Pan Liu, Tian-Mei Yu, Chuan-Min Zhou, Xue-Jie Yu","doi":"10.1080/15548627.2024.2393067","DOIUrl":"10.1080/15548627.2024.2393067","url":null,"abstract":"<p><p>Severe fever with thrombocytopenia syndrome is an emerging viral hemorrhagic fever caused by a tick-borne bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV), with a high case fatality. We previously found that SFTSV nucleoprotein (NP) induces macroautophagy/autophagy to facilitate virus replication. However, the role of NP in antagonizing host innate immunity remains unclear. Mitophagy, a selected form of autophagy, eliminates damaged mitochondria to maintain mitochondrial homeostasis. Here, we demonstrate that SFTSV NP triggers mitophagy to degrade MAVS (mitochondrial antiviral signaling protein), thereby blocking MAVS-mediated antiviral signaling to escape the host immune response. Mechanistically, SFTSV NP translocates to mitochondria by interacting with TUFM (Tu translation elongation factor, mitochondrial), and mediates mitochondrial sequestration into phagophores through interacting with LC3, thus inducing mitophagy. Notably, the N-terminal LC3-interacting region (LIR) motif of NP is essential for mitophagy induction. Collectively, our results demonstrated that SFTSV NP serves as a novel virulence factor, inducing TUFM-mediated mitophagy to degrade MAVS and evade the host immune response.<b>Abbreviation:</b> 3-MA: 3-methyladenine; ACTB: actin beta; co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole, dihydrochloride; DMSO: dimethyl sulfoxide; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GFP: green fluorescent protein; HTNV: Hantan virus; IAV: influenza A virus; IFN: interferon; LAMP1: lysosomal associated membraneprotein 1; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule associatedprotein 1 light chain 3 beta; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MOI: multiplicity of infection; MT-CO2/COXII: mitochondrially encoded cytochrome C oxidase II; NP: nucleoprotein; NSs: nonstructural proteins; poly(I:C): polyinosinic:polycytidylic acid; RIGI: RNA sensor RIG-I; RLR: RIGI-like receptor; SFTSV: severe fever withthrombocytopenia syndrome virus; TCID50: 50% tissue culture infectiousdose; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20:translocase of outer mitochondrial membrane 20; TUFM: Tu translation elongationfactor, mitochondrial.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"102-119"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074822","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":"Myotubularin 2 interacts with SEC23A and negatively regulates autophagy at ER exit sites in Arabidopsis.","authors":"Xinjing Li, Jing Zheng, Jing Su, Lin Wang, Lin Luan, Taotao Wang, Fang Bai, Qing Zhong, Qingqiu Gong","doi":"10.1080/15548627.2024.2394302","DOIUrl":"10.1080/15548627.2024.2394302","url":null,"abstract":"<p><p>Starvation- or stress-induced phosphatidylinositol 3-phosphate (PtdIns3P/PI3P) production at the endoplasmic reticulum (ER) subdomains organizes phagophore assembly and autophagosome formation. Coat protein complex II (COPII) vesicles budding from ER exit site (ERES) also contribute to autophagosome formation. Whether any PtdIns3P phosphatase functions at ERES to inhibit macroautophagy/autophagy is unknown. Here we report Myotubularin 2 (MTM2) of Arabidopsis as a PtdIns3P phosphatase that localizes to ERES and negatively regulates autophagy. MTM2 binds PtdIns3P with its PH-GRAM domain <i>in vitro</i> and acts toward PtdIns3P <i>in vivo</i>. Transiently expressed MTM2 colocalizes with ATG14b, a subunit of the phosphatidylinositol 3-kinase (PtdIns3K) complex, and overexpression of MTM2 blocks autophagic flux and causes over-accumulation of ATG18a, ATG5, and ATG8a. The <i>mtm2</i> mutant has higher levels of autophagy and is more tolerant to starvation, whereas <i>MTM2</i> overexpression leads to reduced autophagy and sensitivity to starvation. The phenotypes of <i>mtm2</i> are suppressed by <i>ATG2</i> mutation, suggesting that MTM2 acts upstream of ATG2. Importantly, MTM2 does not affect the endosomal functions of PtdIns3P. Instead, MTM2 specifically colocalizes with COPII coat proteins and is cradled by the ERES-defining protein SEC16. MTM2 interacts with SEC23A with its phosphatase domain and inhibits COPII-mediated protein secretion. Finally, a role for MTM2 in salt stress response is uncovered. <i>mtm2</i> resembles the halophyte <i>Thellungiella salsuginea</i> in its efficient vacuolar compartmentation of Na⁺, maintenance of chloroplast integrity, and timely regulation of autophagy-related genes. Our findings reveal a balance between PtdIns3P synthesis and turnover in autophagosome formation, and provide a new link between autophagy and COPII function.<b>Abbreviations</b>: ATG: autophagy related; BFA: brefeldin A; BiFC: bimolecular fluorescence complementation; CHX: cycloheximide; ConA: concanamycin A; COPII: coat protein complex II; ER: endoplasmic reticulum; ERES: ER exit site; MS: Murashige and Skoog; MTM: myotubularin; MVB: multivesicular body; PAS: phagophore assembly site; PI: phosphoinositide; TEM: transmission electron microscopy; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"141-159"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037994","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":"Mitochondrial bioenergetics stimulates autophagy for pathological MAPT/Tau clearance in tauopathy neurons.","authors":"Nuo Jia, Dhasarathan Ganesan, Hongyuan Guan, Yu Young Jeong, Sinsuk Han, Gavesh Rajapaksha, Marialaina Nissenbaum, Alexander W Kusnecov, Qian Cai","doi":"10.1080/15548627.2024.2392408","DOIUrl":"10.1080/15548627.2024.2392408","url":null,"abstract":"<p><p>Hyperphosphorylation and aggregation of MAPT (microtubule-associated protein tau) is a pathogenic hallmark of tauopathies and a defining feature of Alzheimer disease (AD). Pathological MAPT/tau is targeted by macroautophagy/autophagy for clearance after being sequestered within autophagosomes, but autophagy dysfunction is indicated in tauopathy. While mitochondrial bioenergetic deficits have been shown to precede MAPT/tau pathology in tauopathy brains, it is unclear whether energy metabolism deficiency is involved in the pathogenesis of autophagy defects. Here, we reveal that stimulation of anaplerotic metabolism restores defective oxidative phosphorylation (OXPHOS) in tauopathy neurons which, strikingly, leads to pronounced MAPT/tau clearance by boosting autophagy functionality through enhancements of mitochondrial biosynthesis and supply of phosphatidylethanolamine for autophagosome biogenesis. Furthermore, early anaplerotic stimulation of OXPHOS elevates autophagy activity and attenuates MAPT/tau pathology, thereby counteracting memory impairment in tauopathy mice. Taken together, our study sheds light on a pivotal role of mitochondrial bioenergetic deficiency in tauopathy-related autophagy defects and suggests a new therapeutic strategy to prevent the buildup of pathological MAPT/tau in AD and other tauopathy diseases.<b>Abbreviation</b>: AA: antimycin A; AD, Alzheimer disease; ATP, adenosine triphosphate; AV, autophagosome/autophagic vacuole; AZ, active zone; Baf-A1: bafilomycin A₁; CHX, cycloheximide; COX, cytochrome c oxidase; DIV, days <i>in vitro</i>; DRG, dorsal root ganglion; ETN, ethanolamine; FRET, Förster/fluorescence resonance energy transfer; FTD, frontotemporal dementia; Gln, glutamine; HA: hydroxylamine; HsMAPT/Tau, human MAPT; IMM, inner mitochondrial membrane; LAMP1, lysosomal-associated membrane protein 1; LIs, lysosomal inhibitors; MDAV, mitochondria-derived autophagic vacuole; MmMAPT/Tau, murine MAPT; NFT, neurofibrillary tangle; OCR, oxygen consumption rate; Omy: oligomycin; OXPHOS, oxidative phosphorylation; PPARGC1A/PGC-1alpha: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PE, phosphatidylethanolamine; phospho-MAPT/tau, hyperphosphorylated MAPT; PS, phosphatidylserine; PISD, phosphatidylserine decarboxylase;SQSTM1/p62, sequestosome 1; STX1, syntaxin 1; SYP, synaptophysin; Tg, transgenic; TCA, tricarboxylic acid; TEM, transmission electron microscopy.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"54-79"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019887","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":"MANF facilitates breast cancer cell survival under glucose-starvation conditions via PRKN-mediated mitophagy regulation.","authors":"Zhenchong Xiong, Lin Yang, Chao Zhang, Weiling Huang, Wenjing Zhong, Jiarong Yi, Jikun Feng, Xiazi Zouxu, Libing Song, Xi Wang","doi":"10.1080/15548627.2024.2392415","DOIUrl":"10.1080/15548627.2024.2392415","url":null,"abstract":"<p><p>During tumor expansion, breast cancer (BC) cells often experience reactive oxygen species accumulation and mitochondrial damage because of glucose shortage. However, the mechanism by which BC cells deal with the glucose-shortage-induced oxidative stress remains unclear. Here, we showed that MANF (mesencephalic astrocyte derived neurotrophic factor)-mediated mitophagy facilitates BC cell survival under glucose-starvation conditions. MANF-mediated mitophagy also promotes fatty acid oxidation in glucose-starved BC cells. Moreover, during glucose starvation, SENP1-mediated de-SUMOylation of MANF increases cytoplasmic MANF expression through the inhibition of MANF's nuclear translocation and hence renders mitochondrial distribution of MANF. MANF mediates mitophagy by binding to PRKN (parkin RBR E3 ubiquitin protein ligase), a key mitophagy regulator, in the mitochondria. Under conditions of glucose starvation, protein oxidation inhibits PRKN activity; nevertheless, the CXXC motif of MANF alleviates protein oxidation in RING II-domain of PRKN and restores its E3 ligase activity. Furthermore, MANF-PRKN interactions are essential for BC tumor growth and metastasis. High MANF expression predicts poor outcomes in patients with BC. Our results highlight the prosurvival role of MANF-mediated mitophagy in BC cells during glucose starvation, suggesting MANF as a potential therapeutic target.<b>Abbreviation:</b> 2DG, 2-deoxy-D-glucose; 5TG, 5-thio-D-glucose; ACSL4/FACL4, acyl-CoA synthetase long chain family member 4; Baf A1, bafilomycin A₁; BRCA, breast cancer; CHX, cycloheximide; DMF, distant metastasis-free; DMFS, distant metastasis-free survival; ECM, extracellular matrix; ER, endoplasmic reticulum; ERS, endoplasmic reticulum stress; F-1,6-BP, fructose-1,6-bisphosphate; FAO, fatty acid oxidation; GSH, reduced glutathione; GSVA, gene set variation analysis; HCC, hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma; IF, immunofluorescence; MANF, mesencephalic astrocyte derived neurotrophic factor; Mdivi-1, mitochondrial division inhibitor 1; MFI, mean fluorescence intensity; NAC, N-acetyl-L-cysteine; OCR, oxygen-consumption rate; OS, overall survival; PMI, SQSTM1/p62-mediated mitophagy inducer; PPP, pentose phosphate pathway; PRKN, parkin RBR E3 ubiquitin protein ligase; RBR, RING in between RING; RFS, relapse-free survival; ROS, reactive oxygen species; SAPLIPs, saposin-like proteins; TCGA, The Cancer Genome Atlas; TNBC, triple-negative breast cancer; WT, wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"80-101"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141989767","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":"Mitophagy as a guardian against cellular aging.","authors":"Tetsushi Kataura, Niall Wilson, Gailing Ma, Viktor I Korolchuk","doi":"10.1080/15548627.2024.2414461","DOIUrl":"10.1080/15548627.2024.2414461","url":null,"abstract":"<p><p>Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N-57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N-57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(-like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy.<b>Abbreviation:</b> IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"249-251"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482857","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":"Nuclear proteasomes as a backup for autophagy: interconnected proteostasis pathways.","authors":"Meiyan Jin, Daniel J Klionsky","doi":"10.1080/15548627.2024.2416261","DOIUrl":"10.1080/15548627.2024.2416261","url":null,"abstract":"<p><p>Protein homeostasis (proteostasis) refers to the balance of the cellular protein environment, tightly regulated by pathways governing protein synthesis, folding, trafficking, and degradation. Growing evidence supports the interconnection of these pathways to ensure the robustness of the proteo-stasis network. A recent study by Park et al. showed that, in macroautophagy/autophagy-deficient cells, the loss of proteasome or nuclear pore components causes synthetic lethality, as cytoplasmic proteins that accumulate under impaired autophagy are transported to the nucleus and degraded by nuclear proteasomes. The authors illustrated the mechanistic basis for why cells with conditions such as Huntington disease, where both autophagy and cytoplasm-to-nuclear shuttling are compromised, are more vulnerable to proteostasis perturbation.<b>Abbreviation</b>: UPR: unfolded protein response; UPS: ubiquitin-proteasome system.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-2"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11702925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive knockout analysis of the RAB family small GTPases reveals an overlapping role of RAB2 and RAB14 in autophagosome maturation.","authors":"Kentaro Haga, Mitsunori Fukuda","doi":"10.1080/15548627.2024.2374699","DOIUrl":"10.1080/15548627.2024.2374699","url":null,"abstract":"<p><p>Macroautophagy, simply referred to below as autophagy, is an intracellular degradation system that is highly conserved in eukaryotes. Since the processes involved in autophagy are accompanied by membrane dynamics, RAB small GTPases, key regulators of membrane trafficking, are generally thought to regulate the membrane dynamics of autophagy. Although more than half of the mammalian RABs have been reported to be involved in canonical and selective autophagy, no consensus has been reached in regard to the role of RABs in mammalian autophagy. Here, we comprehensively analyzed a <i>rab</i>-knockout (KO) library of MDCK cells to reevaluate the requirement for each RAB isoform in basal and starvation-induced autophagy. The results revealed clear alteration of the MAP1LC3/LC3-II level in only four <i>rab</i>-KO cells (<i>rab1</i>-KO, <i>rab2</i>-KO, <i>rab7a</i>-KO, and <i>rab14</i>-KO cells) and identified RAB14 as a new regulator of autophagy, specifically at the autophagosome maturation step. The autophagy-defective phenotype of two of these <i>rab</i>-KO cells, <i>rab2</i>-KO and <i>rab14</i>-KO cells, was very mild, but double KO of <i>rab2</i> and <i>rab14</i> caused a severer autophagy-defective phenotype (greater LC3 accumulation than in single-KO cells, indicating an overlapping role of RAB2 and RAB14 during autophagosome maturation. We also found that RAB14 is phylogenetically similar to RAB2 and that it possesses the same properties as RAB2, i.e. autophagosome localization and interaction with the HOPS subunits VPS39 and VPS41. Our findings suggest that RAB2 and RAB14 overlappingly regulate the autophagosome maturation step through recruitment of the HOPS complex to the autophagosome.<b>Abbreviation:</b> AID2: auxin-inducible degron 2; ATG: autophagy related; BafA1: bafilomycin A₁; CKO: conditional knockout; EBSS: Earle's balanced salt solution; EEA1: early endosome antigen 1; HOPS: homotypic fusion and protein sorting; HRP: horseradish peroxidase; IP: immunoprecipitation; KD: knockdown; KO: knockout; LAMP2: lysosomal-associated membrane protein 2; MDCK: Madin-Darby canine kidney; mAb: monoclonal antibody; MEF: mouse embryonic fibroblast; MTORC1: mechanistic target of rapamycin kinase complex 1; 5-Ph-IAA: 5-phenyl-indole-3-acetic acid; pAb: polyclonal antibody; siRNA: small interfering RNA; SNARE: soluble NSF-attachment protein receptor; TF: transferrin; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"21-36"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494593","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":"Interactors and neighbors of ULK1 complex members.","authors":"Devanarayanan Siva Sankar, Joern Dengjel","doi":"10.1080/15548627.2024.2414386","DOIUrl":"10.1080/15548627.2024.2414386","url":null,"abstract":"<p><p>The ULK1 kinase complex plays a crucial role in autophagosome biogenesis. To identify interactors or regulators of ULK1 complex assembly influencing autophagosome biogenesis, we performed an interaction proteomics screen. Employing both affinity purification and proximity labeling of <i>N</i>- and <i>C</i>-terminal tagged fusion proteins coupled to quantitative mass spectrometry, we identified 317 high-confidence interactors or neighbors of the four ULK1 complex members, including both member-specific and common interactors. Interactions with selective macroautophagy/autophagy receptors indicate the activation of selective autophagy pathways by 90 min of nutrient starvation. Focusing on the ULK1 effector protein BAG2, a common interactor identified by both approaches, we highlight that ULK1 phosphorylates BAG2, supporting the localization of the scaffold and autophagy inducer AMBRA1 to the ER, thereby positively regulating autophagy initiation.<b>Abbreviation</b>: AMBRA1: autophagy and beclin 1 regulator 1; ATG: autophagy related; ER: endoplasmic reticulum; HA: hemagglutinin; KD: knockdown; KO: knockout; MS: mass spectrometry; PTM: posttranslational modification; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1; WIPI2: WD repeat domain, phosphoinositide interacting 2.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"243-245"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482856","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":"Macrophage autophagy protects against acute kidney injury by inhibiting renal inflammation through the degradation of TARM1.","authors":"Xiao-Rong Huang, Lin Ye, Ning An, Chun-Yu Wu, Hong-Luan Wu, Hui-Yuan Li, Yan-Heng Huang, Qiao-Ru Ye, Ming-Dong Liu, La-Wei Yang, Jian-Xing Liu, Ji-Xin Tang, Qing-Jun Pan, Peng Wang, Lin Sun, Yin Xia, Hui-Yao Lan, Chen Yang, Hua-Feng Liu","doi":"10.1080/15548627.2024.2393926","DOIUrl":"10.1080/15548627.2024.2393926","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Macroautophagy/autophagy activation in renal tubular epithelial cells protects against acute kidney injury (AKI). However, the role of immune cell autophagy, such as that involving macrophages, in AKI remains unclear. In this study, we discovered that macrophage autophagy was an adaptive response during AKI as mice with macrophage-specific autophagy deficiency (&lt;i&gt;atg5&lt;/i&gt;&lt;sup&gt;-/-&lt;/sup&gt;) exhibited higher serum creatinine, more severe renal tubule injury, increased infiltration of ADGRE1/F4/80&lt;sup&gt;+&lt;/sup&gt; macrophages, and elevated expression of inflammatory factors compared to WT mice during AKI induced by either LPS or unilateral ischemia-reperfusion. This was further supported by adoptive transfer of &lt;i&gt;atg5&lt;/i&gt;&lt;sup&gt;-/-&lt;/sup&gt; macrophages, but not WT macrophages, to cause more severe AKI in clodronate liposomes-induced macrophage depletion mice. Similar results were also obtained in vitro that bone marrow-derived macrophages (BMDMs) lacking &lt;i&gt;Atg5&lt;/i&gt; largely increased pro-inflammatory cytokine expression in response to LPS and IFNG. Mechanistically, we uncovered that &lt;i&gt;atg5&lt;/i&gt; deletion significantly upregulated the protein expression of TARM1 (T cell-interacting, activating receptor on myeloid cells 1), whereas inhibition of TARM1 suppressed LPS- and IFNG-induced inflammatory responses in &lt;i&gt;atg5&lt;/i&gt;&lt;sup&gt;-/-&lt;/sup&gt; RAW 264.7 macrophages. The E3 ubiquitin ligases MARCHF1 and MARCHF8 ubiquitinated TARM1 and promoted its degradation in an autophagy-dependent manner, whereas silencing or mutation of the functional domains of MARCHF1 and MARCHF8 abolished TARM1 degradation. Furthermore, we found that ubiquitinated TARM1 was internalized from plasma membrane into endosomes, and then recruited by the ubiquitin-binding autophagy receptors TAX1BP1 and SQSTM1 into the autophagy-lysosome pathway for degradation. In conclusion, macrophage autophagy protects against AKI by inhibiting renal inflammation through the MARCHF1- and MARCHF8-mediated degradation of TARM1.&lt;b&gt;Abbreviations:&lt;/b&gt; AKI, acute kidney injury; ATG, autophagy related; Baf, bafilomycin A&lt;sub&gt;1&lt;/sub&gt;; BMDMs, bone marrow-derived macrophages; CCL2/MCP-1, C-C motif chemokine ligand 2; CHX, cycloheximide; CQ, chloroquine; IFNG, interferon gamma; IL, interleukin; IR, ischemia-reperfusion; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; LPS, lipopolysaccharide; MARCHF, membrane associated ring-CH-type finger; NC, negative control; NFKB, nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3, NLR family, pyrin domain containing 3; NOS2, nitric oxide synthase 2, inducible; Rap, rapamycin; Wort, wortmannin; RT-qPCR, real-time quantitative polymerase chain reaction; Scr, serum creatinine; SEM, standard error of mean; siRNA, small interfering RNA; SYK, spleen tyrosine kinase; TARM1, T cell-interacting, activating receptor on myeloid cells 1; TAX1BP1, Tax1 (human T cell leukemia virus type I) binding protein 1; TECs, tubule epithelial cells; TNF, tumor necrosis fact","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"120-140"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142082828","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":"A PRKN-independent mechanism regulating cardiac mitochondrial quality control.","authors":"Wenjuan Wang, Jinbao Liu, Jie Li, Huabo Su","doi":"10.1080/15548627.2024.2423329","DOIUrl":"10.1080/15548627.2024.2423329","url":null,"abstract":"<p><p>PRKN-dependent mitophagy plays a crucial role in maintaining mitochondrial health. Yet, PRKN-deficient mice do not exhibit mitochondrial and cardiac phenotypes at baseline, suggesting the existence of other mitochondrial ubiquitin (Ub) ligases. Here, we discuss our recent work identifying RNF7/RBX2 as a novel mitochondrial Ub ligase. Upon mitochondrial depolarization, RNF7 proteins are recruited to the mitochondria, where they directly ubiquitinate mitochondrial proteins and stabilize PINK1 expression, thereby promoting the clearance of damaged mitochondria and regulating mitochondrial turnover in the heart. The actions of RNF7 in mitochondria do not require PRKN. Ablation of <i>Rnf7</i> in mouse hearts results in severe mitochondrial dysfunction and heart failure. Our findings demonstrate that RNF7 is indispensable for mitochondrial turnover and cardiac homeostasis. These results open new avenues for exploring new PRKN-independent pathways that regulate mitophagy, which could have significant implications for developing therapeutic interventions for cardiac diseases.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"254-256"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11702962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}