Autophagy最新文献

{"title":"Baicalein tethers CD274/PD-L1 for autophagic degradation to boost antitumor immunity.","authors":"Bingjie Hao, Shumeng Lin, Haipeng Liu, Junfang Xu, Li Chen, Tiansheng Zheng, Wen Zhang, Yifang Dang, Russel J Reiter, Chaoqun Li, Hong Zhai, Qing Xia, Lihong Fan","doi":"10.1080/15548627.2024.2439657","DOIUrl":"10.1080/15548627.2024.2439657","url":null,"abstract":"<p><p>Immune checkpoint inhibitors, especially those targeting CD274/PD-L1yield powerful clinical therapeutic efficacy. Thoughmuch progress has been made in the development of antibody-basedCD274 drugs, chemical compounds applied for CD274degradation remain largely unavailable. Herein,baicalein, a monomer of traditional Chinese medicine, isscreened and validated to target CD274 and induces itsmacroautophagic/autophagic degradation. Moreover, we demonstrate thatCD274 directly interacts with MAP1LC3B (microtubule associatedprotein 1 light chain 3 beta). Intriguingly, baicalein potentiatesCD274-LC3 interaction to facilitate autophagic-lysosomal degradationof CD274. Importantly, targeted CD274. degradation via baicaleininhibits tumor development by boosting T-cell-mediated antitumorimmunity. Thus, we elucidate a critical role of autophagy-lysosomalpathway in mediating CD274 degradation, and conceptually demonstratethat the design of a molecular \"glue\" that tethers the CD274-LC3interaction is an appealing strategy to develop CD274 inhibitors incancer therapy.<b>Abbreviations</b>: ATTECs: autophagy-tethering compounds; AUTACs: AUtophagy-TArgeting Chimeras; AUTOTACs: AUTOphagy-TArgeting Chimeras; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; BiFC: bimolecular fluorescence complementation; BafA1: bafilomycin A₁; CD274/PD-L1/B7-H1: CD274 molecule; CQ: chloroquine; CGAS: cyclic GMP-AMP synthase; DAPI: 4'6-diamino-2-phenylindole; FITC: fluorescein isothiocyanate isomer; GFP: green fluorescent protein; GZMB: granzyme B; IHC: immunohistochemistry; ICB: immune checkpoint blockade; KO: knockout; KD: equilibrium dissociation constant; LYTAC: LYsosome-TArgeting Chimera; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MST: microscale thermophoresis; NFAT: nuclear factor of activated T cells; NFKB/NF-kB: nuclear factor kappa B; NSCLC: non-small-cell lung cancer; PDCD1: programmed cell death 1; PROTACs: PROteolysis TArgeting Chimeras; PRF1: perforin 1; PE: phosphatidylethanolamine; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; STAT: signal transducer and activator of transcription; SPR: surface plasmon resonance; TILs: tumor-infiltrating lymphocyte; TME: tumor microenvironment.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"917-933"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878933","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":"Autophagy induction by piplartine ameliorates axonal degeneration caused by mutant HSPB1 and HSPB8 in Charcot-Marie-Tooth type 2 neuropathies.","authors":"Angela Sisto, Tamira van Wermeskerken, Michael Pancher, Pamela Gatto, Bob Asselbergh, Ágata Sofia Assunção Carreira, Vicky De Winter, Valentina Adami, Alessandro Provenzani, Vincent Timmerman","doi":"10.1080/15548627.2024.2439649","DOIUrl":"10.1080/15548627.2024.2439649","url":null,"abstract":"<p><p>HSPB1 [heat shock protein family B (small) member 1] and HSPB8 are essential molecular chaperones for neuronal proteostasis, as they prevent protein aggregation. Mutant HSPB1 and HSPB8 primarily harm peripheral neurons, resulting in axonal Charcot-Marie-Tooth neuropathies (CMT2). Macroautophagy/autophagy is a shared mechanism by which HSPB1 and HSPB8 mutations cause neuronal dysfunction. Autophagosome formation is reduced in mutant HSPB1-induced pluripotent stem-cell-derived motor neurons from CMT type 2F patients. Likewise, the HSPB8^K141N knockin mouse model, mimicking CMT type 2 L, exhibits axonal degeneration and muscle atrophy, with SQSTM1/p62-positive deposits. We show here that mouse embryonic fibroblasts isolated from a HSPB8^K141N/green fluorescent protein (GFP)-LC3 model have diminished autophagosome production under conditions of MTOR inhibition. To correct the autophagic deficits in the HSPB1 and HSPB8 models, we screened by high-throughput autophagosome quantification the repurposing Spectrum Collection library for molecules that could boost the autophagic activity above the canonical MTOR inhibition. Hit compounds were validated on motor neurons obtained by differentiation of HSPB1^P182L and HSPB8^K141N patient-derived induced pluripotent stem cells, focusing on autophagy induction as well as neurite network density, axonal degeneration, and mitochondrial morphology. We identified molecules that specifically stimulate autophagosome formation in the HSPB8^K141N cells, without affecting autophagy flux. Two top lead compounds induced autophagy and reduced axonal degeneration, thus promoting neuronal network maturation in the CMT2 patient-derived motor neurons. Based on these findings, the phenotypical screen revealed that piplartine rescued autophagy deficiencies in both the HSPB1 and HSPB8 models, demonstrating autophagy induction as an effective therapeutic strategy for CMT neuropathies and other chaperonopathies.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1116-1143"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142855869","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":"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":"1075-1095"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916455","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":"Chaperone-mediated autophagy contributes to chromosomal stability by controlling TTC28 degradation.","authors":"Ge Zhang, Wei Tian, Dajun Deng","doi":"10.1080/15548627.2025.2456685","DOIUrl":"10.1080/15548627.2025.2456685","url":null,"abstract":"<p><p>While macroautophagy (autophagy) contributes to maintaining chromosomal stability via multiple pathways, including regulating chromatin ubiquitination and cytoplasmic DNA fragment degradation, the impacts of microautophagy and chaperone-mediated autophagy (CMA) on maintaining chromosomal stability are not known. The <i>TTC28</i> (tetratricopeptide repeat domain 28) gene is frequently mutated and downregulated in human cancers. The molecular mass of the TTC28 protein is 271 kDa, which makes its functional study very difficult. Recently, we reported that TTC28 plays a key role in maintaining chromosomal stability, probably through regulating mitosis and cytokinesis, and that <i>TTC28</i> downregulation may contribute to the high chromosomal instability (CIN) of cancer cells, according to the results of serial experiments and bioinformatics analyses. Notably, our findings demonstrate that TTC28 is a substrate of CMA and that the CMA pathway also plays a role in maintaining chromosomal stability in a TTC28-dependent manner. These findings demonstrate that CMA-mediated degradation is a master regulator of the ability of TTC28 to maintain genome stability.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1165-1166"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076673","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":"Flavivirus NS2A orchestrates reticulophagy to enhance viral pathogenicity.","authors":"Linliang Zhang, Yali Qin, Mingzhou Chen","doi":"10.1080/15548627.2025.2457112","DOIUrl":"10.1080/15548627.2025.2457112","url":null,"abstract":"<p><p>Selective endoplasmic reticulum (ER) autophagy (reticulophagy) is essential for maintaining ER homeostasis. The E3 ligase AMFR facilitates the ubiquitination of the reticulophagy receptor RETREG1/FAM134B, thereby promoting the dynamic flux of the reticulophagy process. Flaviviruses exploit the ER during their replication cycles, highlighting the importance of ER quantity and accessibility in flavivirus infections. However, the role of reticulophagy in viral replication and the complex mechanisms by which viruses modulate reticulophagy to enhance pathogenicity remain poorly understood. In a recent study, we demonstrate that the Zika virus (ZIKV) hijacks the ER-located E3 ligase AMFR to ubiquitinate NS2A, leading to the degradation of the key reticulophagy receptor RETREG1. This inhibition of the reticulophagy process promotes virus-induced microcephaly in human brain organoids and enhances viral pathogenicity in mouse models. Notably, the AMFR-mediated ubiquitination of ZIKV-NS2A and its functional interaction with RETREG1 are conserved across the NS2A of other flaviviruses, including those from Dengue virus, West Nile virus, and Japanese encephalitis virus.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1167-1168"},"PeriodicalIF":0.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191531","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":"ATG9 inhibits <i>Rickettsia</i> binding to the host cell surface by blocking the rOmpB-XRCC6/KU70 interaction.","authors":"Chen Chen, Guoxu Liu, Kehan Xu, Aibao Chen, Ziyang Cheng, Xueping Yan, Ting Zhang, Yan Sun, Tian Yu, Jiayao Wang, Shuangshuang Luo, Weiting Zhou, Shengqun Deng, Yan Liu, Yanan Yang","doi":"10.1080/15548627.2025.2496363","DOIUrl":"https://doi.org/10.1080/15548627.2025.2496363","url":null,"abstract":"<p><p>ickettsiae are tick-borne pathogens that infect human hosts through poorly characterized mechanisms. Herein, we report that ATG9 (autophagy related 9) plays a previously unrecognized role in inhibiting Rickettsia binding to the host cell surface. Unexpectedly, this new function of ATG9 is likely independent of macroautophagy/autophagy. Instead, ATG9 acts as a host defending factor by binding to XRCC6/KU70, a receptor of the Rickettsia outer-membrane protein rOmpB. Both ATG9 and rOmpB bind to the DNA-binding domain of XRCC6, suggesting a competitive role for ATG9 occupying the binding site of rOmpB to abrogate Rickettsia binding. Furthermore, we show that rapamycin transcriptionally activates ATG9 and inhibits rOmpB-mediated infection in a mouse model. Collectively, our study reveals a novel innate mechanism regulating Rickettsia infection and suggests that agonists of ATG9 May be useful for developing therapeutic strategies for the intervention of rickettsial diseases.<b>Abbreviation</b>: APEX2: apurinic/apyrimidinic endodeoxyribonuclease 2; ATG: autophagy related; BafA1: bafilomycin A1; CQ: chloroquine; E. coli: Escherichia coli; GST: glutathione S-transferase; ICM: immunofluorescence confocal microscopy; IP-Mass: immunoprecipitation-mass spectrometry; KD: knockdown; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; rOmpB: rickettsial outer membrane protein B; SAP: SAF-A/B, Acinus, and PIAS; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; VWA: von Willebrand factor A; XRCC6/KU70: X-ray repair cross complementing 6.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031083","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":"ATG9A controls all stages of autophagosome biogenesis.","authors":"Ruheena Javed, Muriel Mari, Einar Trosdal, Thabata Lopes Alberto Duque, Masroor Paddar, Lee Allers, Prithvi Akepati, Michal H Mudd, Fulvio Reggiori, Vojo Deretic","doi":"10.1080/15548627.2025.2494802","DOIUrl":"https://doi.org/10.1080/15548627.2025.2494802","url":null,"abstract":"<p><p>Canonical autophagy is an intracellular pathway that degrades and recycles cellular components. A key step of this pathway is the formation of double-membraned organelles, known as autophagosomes, an emblematic feature of macroautophagy. For convenience, the formation of autophagosomes can be categorized into sequential steps, initiation (X), expansion (Y) and closure (Z). ATG9A is an integral membrane protein known for its role in the X and Y steps. whereby it organizes phagophore membrane assembly and its growth. Here, we report a previously unappreciated function of mammalian ATG9A in directing the last step Z. In particular, ATG9A partners with the key ESCRT-III component CHMP2A through IQGAP1 to facilitate autophagosome closure. Thus, ATG9A orchestrates all stages of autophagosome membrane biogenesis, from phagophore initiation to its closure. This makes ATG9A a unique ATG factor that works as a central hub in autophagosome biogenesis.<b>Abbreviation</b>: ATG9A autophagy related 9A; CCCP carbonyl cyanide m-chlorophenylhydrazone; Co-IP co-immunoprecipitation; ESCRT endosomal sorting complexes required for transport; EBSS Earle's balanced salt solution; ER endoplasmic reticulum; HCM high-content microscopy; HT HaloTag; LC-MS/MS liquid chromatography-tandem mass spectrometry; KO knockout; MPL membrane permeant ligand; MIL membrane impermeant ligand; Mtb Mycobacterium tuberculosis; SolVit sealing of organellar limiting membranes in vitro; TMR tetramethylrhodamine; WT wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144009743","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":"SMAD3 and PINK1 constitute a new positive feedback loop in regulation of mitophagy.","authors":"Mingzhu Tang, Guang Lu, Han-Ming Shen","doi":"10.1080/15548627.2025.2496364","DOIUrl":"https://doi.org/10.1080/15548627.2025.2496364","url":null,"abstract":"<p><p>Mitophagy, selective degradation of dysfunctional mitochondria by the autophagy-lysosome pathway, is critical for maintaining cellular homeostasis. In recent years, significant progress has been made in understanding how PINK1 (PTEN-induced kinase 1)-mediated phosphorylation and the E3 ubiquitin (Ub) ligase (PRKN/parkin)-mediated ubiquitination form a positive feedforward loop in control of mitophagy. Nevertheless, a fundamental question remains: How is PINK1 transcriptionally modulated under mitochondrial stress to finely support mitophagy? Recently, we unveiled a novel mechanism in control of <i>PINK1</i> transcription by SMAD3 (SMAD family member 3), an essential component of the TGFB/TGFβ (transforming growth factor beta)-SMAD signaling pathway. Upon mitochondrial depolarization, SMAD3 is activated through PINK1-mediated phosphorylation of SMAD3 at serine 423/425 independent of canonical TGFB signaling. More importantly, the SMAD3-PINK1 regulatory axis appears to functionally provide a pro-survival mechanism against mitochondrial stress. Therefore, PINK1 and SMAD3 constitute a newly discovered positive feedforward loop to regulate mitophagy, highlighting the need for further exploring the crosstalk between TGFB-SMAD signaling and mitophagy.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060321","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 RETREG1/FAM134B isoform switch regulates reticulophagy during myogenesis.","authors":"Viviana Buonomo, Michele Cillo, Paolo Grumati","doi":"10.1080/15548627.2025.2494803","DOIUrl":"https://doi.org/10.1080/15548627.2025.2494803","url":null,"abstract":"<p><p>During skeletal muscle development, the sarcoplasmic reticulum forms through the homotypic fusion of ER membranes from individual myoblasts. This involves significant ER remodeling, characterized by an overhaul of its proteomic landscape and the activation of reticulophagy. We described how RETREG1/FAM134B is implicated in both shaping ER morphology and degrading ER membranes through reticulophagy. Following myoblast differentiation, the classic RETREG1/FAM134B1 undergoes lysosomal degradation and is progressively replaced by the shorter RETREG1/FAM134B2 isoform. RETREG1/FAM134B2 is a truncated variant of RETREG1/FAM134B1 maintaining an identical C-terminal region, including the functional LIR, but with a partial loss of its reticulon homology domain. The switch between these two isoforms plays a crucial role in ER morphology and muscle development. Re-expressing <i>Retreg1/Fam134b2</i> in <i>retreg1/fam134b</i>-knockout myoblasts is both necessary and sufficient to rescue the abnormal proteomic landscape and prevent ER dilation. Conversely, the re-expression of <i>Retreg1/Fam134b1</i> only partially rescues ER defects. We highlighted the role of RETREG1/FAM134B isoforms and reticulophagy in maintaining proper ER dynamics during myogenesis.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031617","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":"BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation.","authors":"Sangseob Kim, Cheoljun Choi, Yeonho Son, Junhyuck Lee, Sungug Joo, Yun-Hee Lee","doi":"10.1080/15548627.2025.2487035","DOIUrl":"10.1080/15548627.2025.2487035","url":null,"abstract":"<p><p>Adipose tissue macrophages (ATMs) are key cellular components that respond to nutritional excess, contributing to obesity-induced inflammation and insulin resistance. However, the mechanisms underlying macrophage polarization and recruitment in adipose tissue during obesity remain unclear. In this study, we investigated mitophagy-dependent metabolic reprogramming in ATMs and identified a crucial role of the mitophagy receptor BNIP3 in regulating macrophage polarization in response to obesity. Mitophagic flux in ATMs increased following 12 weeks of high-fat diet (HFD) feeding, with <i>Bnip3</i> levels upregulated in a HIF1A dependent manner, without affecting other mitophagy receptors. Macrophage-specific <i>bnip3</i> knockout reduced HFD-induced adipose tissue inflammation and improved glucose tolerance and insulin sensitivity. Mechanistically, hypoxic conditions <i>in vitro</i> induced HIF1A-BNIP3-mediated mitophagy and glycolytic shift in macrophages. Furthermore, HIF1A-BNIP3 signaling-enhanced lipopolysaccharide-induced pro-inflammatory activation in macrophages. These findings demonstrate that BNIP3-mediated mitophagy regulates the glycolytic shift and pro-inflammatory polarization in macrophages and suggest that BNIP3 could be a therapeutical target for obesity-related metabolic diseases.<b>Abbreviation:</b> 2-DG: 2-deoxyglucose; ACADM/MCAD: acyl-CoA dehydrogenase medium chain; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; ATMs: adipose tissue macrophages; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CLS: crown-like structure; CoCl₂: cobalt(II) chloride; COX4/COXIV: cytochrome c oxidase subunit 4; ECAR: extracellular acidification rate; ECM: extraceullular matrix; gWAT: gonadal white adipose tissue; HFD: high-fat diet; HIF1A/HIF-1 α: hypoxia inducible factor 1 subunit alpha; IL1B/IL-1β: interleukin 1 beta; ITGAM/CD11B: integrin subunit alpha M; KO: knockout; LAMs: lipid-associated macrophages; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MRC1/CD206: mannose receptor C-type 1; mtDNA: mitochondrial DNA; NCD: normal chow diet; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced kinase 1; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PTPRC/CD45: protein tyrosine phosphatase receptor type C; SVFs: stromal vascular fractions; TEM: transmission electron microscopy; TMRM: tetramethylrhodamine methyl ester; TOMM20: Translocase of outer mitochondrial membrane 20; TREM2: triggering receptor expressed on myeloid cells 2; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-19"},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805047","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}