Autophagy最新文献

{"title":"T16G12.6/IMPORTIN 13-mediated cytoplasm-to-nucleus transport of the THAP transcription factor LIN-15B controls autophagy and lysosome function in <i>C. elegans</i>.","authors":"Xiaoli Ma, Xiaomeng Gou, Hong Zhang","doi":"10.1080/15548627.2025.2482724","DOIUrl":"10.1080/15548627.2025.2482724","url":null,"abstract":"<p><p>Transcriptional regulation of genes involved in the macroautophagy/autophagy-lysosome pathway acts as an important mechanism for controlling autophagy activity. The factors that globally regulate autophagy activity at the transcriptional level during <i>C. elegans</i> development remain unknown. Here we showed that the THAP domain-containing transcription factor LIN-15B modulates autophagy activity during <i>C. elegans</i> development. Loss of function of <i>lin-15B</i> suppresses the autophagy defect caused by impaired autophagosome maturation and promotes lysosome biogenesis and function. LIN-15B maintains the repressed state of genes involved in the autophagy pathway. Accordingly, loss of function of <i>lin-15B</i> upregulates a plethora of genes involved in autophagosome formation and maturation as well as lysosome biogenesis and function. The cytoplasm-to-nucleus translocation of LIN-15B is mediated by the T16G12.6/IMPORTIN 13/IPO-13 receptor and modulated by nutrient status. Our study uncovers that LIN-15B integrates environmental cues into transcriptional control of a network of genes involved in autophagy in <i>C. elegans</i>.<b>Abbreviations:</b> ATG: autophagy related; DIC: differential interference contrast; EPG: ectopic PGL granules; ER: endoplasmic reticulum; FOXO: forkhead box O; GFP: green fluorescent protein; SQST-1: SeQueSTosome related 1; SynMuv: synthetic multivulva; IPO-13: importin 13; TFEB: transcription factor EB.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702500","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":"First responder to starvation: microreticulophagy clears aberrant membrane proteins in quick bites.","authors":"Yaneris Alvarado Cartagena, Valeriya Gyurkovska, Nava Segev","doi":"10.1080/15548627.2025.2487675","DOIUrl":"https://doi.org/10.1080/15548627.2025.2487675","url":null,"abstract":"<p><p>Cells can use two different pathways for recycling their non-essential components in the lysosome during nutritional stress: macroautophagy and microautophagy. While the well-established macroautophagy pathway requires de novo formation of the double-membrane autophagosome, microautophagy involves direct engulfment of cargo by the lysosomal membrane. Recently, using a yeast model, we identified a novel microreticulophagy pathway induced by nutritional stress that selectively clears aberrant membrane proteins that accumulate during normal growth. This effective clearance occurs rapidly and precedes the degradation of normal ER- or mitochondrial-membrane proteins by macroautophagy. We showed that the nutritional-stress induced selective microreticulophagy pathway requires the ubiquitin-ligase Rsp5, its adaptor Ssh4, and the ESCRT complex. Moreover, live-cell fluorescence microscopy with high temporal and special resolution demonstrated that individual microautophagy events occur within seconds. Thus, cells use the effective microreticulophagy pathway to dispose of misfolded or excess membrane proteins as a first response to starvation. If the stress persists, the more costly macroautophagy pathway is activated for degrading normal cellular components. These findings point to an intricate interplay between microautophagy and macroautophagy during nutritional stress, which optimizes stress responses and could have significant implications for understanding how cells maintain homeostasis or progress to disease states.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766073","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":"Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.","authors":"Chih-Yao Chung, Kritarth Singh, Preethi Sheshadri, Gabriel E Valdebenito, Anitta R Chacko, María Alicia Costa Besada, Xiao Fei Liang, Lida Kabir, Robert D S Pitceathly, Gyorgy Szabadkai, Michael R Duchen","doi":"10.1080/15548627.2024.2437908","DOIUrl":"10.1080/15548627.2024.2437908","url":null,"abstract":"<p><p>Mitochondrial DNA (mtDNA) encodes genes essential for oxidative phosphorylation. The m.3243A>G mutation causes severe disease, including myopathy, lactic acidosis and stroke-like episodes (MELAS) and is the most common pathogenic mtDNA mutation in humans. We have previously shown that the mutation is associated with constitutive activation of the PI3K-AKT-MTORC1 axis. Inhibition of this pathway in patient fibroblasts reduced the mutant load, rescued mitochondrial bioenergetic function and reduced glucose dependence. We have now investigated the mechanisms that select against the mutant mtDNA under these conditions. Basal macroautophagy/autophagy and lysosomal degradation of mitochondria were suppressed in the mutant cells. Pharmacological inhibition of any step of the PI3K-AKT-MTORC1 pathway activated mitophagy and progressively reduced m.3243A>G mutant load over weeks. Inhibition of autophagy with bafilomycin A₁ or chloroquine prevented the reduction in mutant load, suggesting that mitophagy was necessary to remove the mutant mtDNA. Inhibition of the pathway was associated with metabolic remodeling - mitochondrial membrane potential and respiratory rate improved even before a measurable fall in mutant load and proved crucial for mitophagy. Thus, maladaptive activation of the PI3K-AKT-MTORC1 axis and impaired autophagy play a major role in shaping the presentation and progression of disease caused by the m.3243A>G mutation. Our findings highlight a potential therapeutic target for this otherwise intractable disease.<b>Abbreviation</b>: ΔΨ_m: mitochondrial membrane potential; 2DG: 2-deoxy-D-glucose; ANOVA: analysis of variance; ARMS-qPCR: amplification-refractory mutation system quantitative polymerase chain reaction; Baf A1: bafilomycin A₁; BSA: bovine serum albumin; CQ: chloroquine; Cybrid: cytoplasmic hybrid; CYCS: cytochrome c, somatic; DCA: dichloroacetic acid; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethylsulfoxide; EGFP: enhanced green fluorescent protein; LC3B-I: carboxy terminus cleaved microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated microtubule-associated protein 1 light chain 3 beta; LY: LY290042; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; MFC: mitochondrial fragmentation count; mt-Keima: mitochondrial-targeted mKeima; mtDNA: mitochondrial DNA/mitochondrial genome; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OA: oligomycin+antimycin A; OxPhos: oxidative phosphorylation; DPBS: Dulbecco's phosphate-buffered saline; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PPARGC1B/PGC-1β: PPARG coactivator 1 beta; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; qPCR: quantitative polymerase chain reaction; RNA-seq: RNA sequencing; RP: rapamycin; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; WT: wild-type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"881-896"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820265","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":"TGFB signaling induces mitophagy via PLSCR3-mediated cardiolipin externalization in conjunction with a BNIP3L/NIX-, BNIP3-, and FUNDC1-dependent mechanism.","authors":"Jiong Yan, Xin Chen, Swati Choksi, Zheng-Gang Liu","doi":"10.1080/15548627.2025.2483441","DOIUrl":"10.1080/15548627.2025.2483441","url":null,"abstract":"<p><p>Selective clearance of damaged mitochondria through mitophagy is crucial for the maintenance of mitochondrial homeostasis. While mitophagy can be activated by various mitochondrial toxins, the physiologically relevant signal that triggers mitophagy is less studied. TGFB/TGFβ signaling has been linked to autophagic induction, but its specific role in mitophagy is not well understood. Here, we discovered a novel mitophagy induction paradigm stimulated by TGFB1. The mitophagic response is exclusively mediated by SMAD2, SMAD3, and SMAD4 underlying the TGFB receptor signaling. The transcriptional regulation activates genes involved in the canonical autophagic pathway which is required for the TGFB1-induced mitophagy. Moreover, TGFB1 signaling promotes mitophagic flux by upregulating PLSCR3 that externalizes cardiolipin in conjunction with the MAP1LC3/LC3/GABARAPs-interacting receptor proteins (BNIP3L/NIX, BNIP3, and FUNDC1)-dependent mechanism. Overall, our study characterized the essential components engaged in the TGFB1-induced mitophagy and demonstrated that TGFB is an important signal that induces mitophagy.<b>Abbreviations</b> ATG5: autophagy related 5; ATG8: mammalian homolog of yeast Atg8; ATG9A: autophagy related 9A; ATG13: autophagy related 13; ATG101: autophagy related 101; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; Cardiolipin: 1,3-bis(<i>sn</i>-3'-phosphatidyl)-<i>sn</i>-glycerol; CERS1: ceramide synthase 1; FUNDC1: FUN14 domain containing 1; GABARAP: GABA type A receptor-associated protein; GABARAPL1: GABA type A receptor-associated protein like 1; GABARAPL2: GABA type A receptor-associated protein like 2; GLS: glutaminase; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MitoIP: mitochondrial immunoprecipitation; MMP: mitochondrial membrane potential; NRBF2: nuclear receptor binding factor 2; OPTN: optineurin; PINK1: PTEN induced kinase 1; PLSCR3: phospholipid scramblase 3; PRKN: parkin RBR E3 ubiquitin protein ligase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; TGFB/TGFβ: transforming growth factor beta; ULK1: unc-51 like autophagy activating kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677458","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":"Avian TRIM13 attenuates antiviral innate immunity by targeting MAVS for autophagic degradation.","authors":"Peng Zhou, Qingxiang Zhang, Yueshan Yang, Dong Chen, Anan Jongkaewwattana, Hui Jin, Hongbo Zhou, Rui Luo","doi":"10.1080/15548627.2024.2426114","DOIUrl":"10.1080/15548627.2024.2426114","url":null,"abstract":"<p><p>MAVS (mitochondrial antiviral signaling protein) is a crucial adaptor in antiviral innate immunity that must be tightly regulated to maintain immune homeostasis. In this study, we identified the duck <i>Anas platyrhynchos domesticus</i> TRIM13 (ApdTRIM13) as a novel negative regulator of duck MAVS (ApdMAVS) that mediates the antiviral innate immune response. Upon infection with RNA viruses, ApdTRIM13 expression increased, and it specifically binds to ApdMAVS through its TM domain, facilitating the degradation of ApdMAVS in a manner independent of E3 ligase activity. Furthermore, ApdTRIM13 recruits the autophagic cargo receptor duck SQSTM1 (ApdSQSTM1), which facilitates its interaction with ApdMAVS independent of ubiquitin signaling, and subsequently delivers ApdMAVS to phagophores for degradation. Depletion of ApdSQSTM1 reduces ApdTRIM13-mediated autophagic degradation of ApdMAVS, thereby enhancing the antiviral immune response. Collectively, our findings reveal a novel mechanism by which ApdTRIM13 regulates type I interferon production by targeting ApdMAVS for selective autophagic degradation mediated by ApdSQSTM1, providing insights into the crosstalk between selective autophagy and innate immune responses in avian species.<b>Abbreviation</b>: 3-MA: 3-methyladenine; ATG5: autophagy related 5; baf A1: bafilomycin A1; BECN1: beclin 1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CARD: caspase recruitment domain; co-IP: co-immunoprecipitation; DEFs: duck embryonic fibroblasts; DTMUV: duck Tembusu virus; eGFP: enhanced green fluorescent protein; hpi: hours post infection; IFIH1/MDA5: interferon induced with helicase C domain 1; IFN: interferon; IKBKE/IKKε: inhibitor of nuclear factor kappa B kinase subunit epsilon; IP: immunoprecipitation; IRF7: interferon regulatory factor 7; ISRE: interferon-stimulated response element; mAb: monoclonal antibody; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; NBR1: NBR1 autophagy cargo receptor; NFKB: nuclear factor kappa B; pAb: polyclonal antibody; poly(I:C): Polyriboinosinic polyribocytidylic acid; RIGI: RNA sensor RIG-I; RLR: RIGI-like-receptor; SeV: sendai virus; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 binding protein 1; TBK1: TANK binding kinase 1; TCID50: 50% tissue culture infectious dose; TM: tansmembrane; TOLLIP: toll interacting protein; TRIM: tripartite motif containing; UBA: ubiquitin-associated domain; Ub: ubiquitin; VSV: vesicular stomatitis virus; WT: wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"754-770"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607137","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":"USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis.","authors":"Sen Kang, Shuxin Liu, Xian Dong, Haoyu Li, Yuanyi Qian, Anna Dai, Wentao He, Xiaojun Li, Qianming Chen, Huiming Wang, Pei-Hui Ding","doi":"10.1080/15548627.2024.2429371","DOIUrl":"10.1080/15548627.2024.2429371","url":null,"abstract":"<p><p>Periodontitis, a prevalent and chronic inflammatory disease, is intricately linked with macroautophagy/autophagy, which has a dual role in maintaining periodontal homeostasis. Despite its importance, the precise interplay between autophagy and periodontitis pathogenesis remains to be fully elucidated. In this study, our investigation revealed that the ubiquitination of RAB7A, mediated by reduced levels of the deubiquitinating enzyme USP4 (ubiquitin specific peptidase 4), disrupts normal lysosomal trafficking and autophagosome-lysosome fusion, thereby contributing significantly to periodontitis progression. Specifically, through genomic and histological analysis of clinical gingival samples, we observed a decreased RAB7A expression and impaired autophagic activity in periodontitis. This was further substantiated through experimental periodontitis mice, where RAB7A inactivation was shown to directly affect autophagy efficiency and drive periodontitis progression. Next, we explored the function of active RAB7A to promote lysosomal trafficking dynamics and autophagosome-lysosome fusion, which was inhibited by RAB7A ubiquitination in macrophages stimulated by <i>Porphyromonas gingivalis</i> (<i>P. g</i>.), one of the keystone pathogens of periodontitis. Last, by proteomics analysis, we revealed that the ubiquitination of RAB7A was mediated by USP4 and validated that upregulation of USP4 could attenuate periodontitis in vivo. In conclusion, these findings highlight the interaction between USP4 and RAB7A as a promising target for therapeutic intervention in managing periodontal diseases.<b>Abbreviation:</b> 3-MA: 3-methyladenine; Baf A1:bafilomycin A₁; BECN1: beclin 1, autophagy related; CEJ-ABC: cementoenamel junctionto alveolar bone crest; IL1B/IL-1β: interleukin 1 beta; KD:knockdown; LPS: lipopolysaccharide; MOI: multiplicity of infection;OE: overexpression; <i>P.g</i>.: <i>Porphyromonasgingivalis</i>; RILP: Rabinteracting lysosomal protein; ScRNA-seq: single-cell RNA sequencing; SQSTM1/p62: sequestosome 1; <i>S.s</i>.: <i>Streptococcus sanguinis</i>; USP4:ubiquitin specific peptidase 4.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"771-788"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815157","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":"RNF144A inhibits autophagy by targeting BECN1 for degradation during <i>L. monocytogenes</i> infection.","authors":"Bo Yang, Mengyang Shen, Chen Lu, Yi Wang, Xin Zhao, Qunmei Zhang, Xiao Qin, Jinyong Pei, Hui Wang, Jie Wang","doi":"10.1080/15548627.2024.2429380","DOIUrl":"10.1080/15548627.2024.2429380","url":null,"abstract":"<p><p><i>Listeria monocytogenes (L. monocytogenes, Lm)</i> is widely used in the laboratory as an infection model for the research on pathogenesis and host defense against gram-positive intracellular bacteria. Macroautophagy (called simply \"autophagy\" hereafter), is important in the host defense against pathogens, such as bacteria, viruses, and parasites. BECN1 plays a pivotal role in the initiation of autophagy and accumulating evidence indicates that post-translational modifications of BECN1 provide multiple strategies for autophagy regulation. In this study, we demonstrated that the RING1-IBR-RING2 (RBR) family member RNF144A (ring finger protein 144A), which was induced by <i>Lm</i> infection, promoted <i>Lm</i> infection in an autophagy-dependent but STING1-independent pattern. <i>rnf144a</i> deficiency in mice protected mice from <i>Lm</i> infection with inhibited innate immune responses. Interestingly, RNF144A decreased <i>Lm</i>-induced autophagosome accumulation. Mechanistic investigation indicated that RNF144A interacted with BECN1 and promoted its K48-linked ubiquitination, leading to the subsequent proteasome-dependent degradation of BECN1 and reduced autophagosome accumulation. Further study demonstrated that RNF144A promoted the ubiquitination of BECN1 at K117 and K427, and these two ubiquitination sites were essential to the role of BECN1 in autophagy and Lm infection. Thus, our findings suggested a new regulator in intracellular bacterial infection and autophagy, which may contribute to our understanding of host defense against intracellular bacterial infection via autophagy.<b>Abbreviations</b>: ATG3: autophagy related 3; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG10: autophagy related 10; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; Baf A₁: bafilomycin A₁; BECN1: beclin 1; BMDC: bone marrow-derived dendritic cell; BMDM: bone marrow-derived macrophage; CFUs: colony-forming units; CHX: cycloheximide; CQ: chloroquine; CXCL10/IP-10: C-X-C motif chemokine ligand 10; EBSS: Earle's balanced salt solution; ELISA: enzyme-linked immunosorbent assay; IFIT1/ISG56: interferon induced protein with tetratricopeptide repeats 1; IFNB/IFN-β: interferon beta; IL6: interleukin 6; IRF3, interferon regulatory factor 3; Lm: <i>L. monocytogenes</i>; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MOI: multiplicity of infection; PLA: proximity ligation assay; PMA: phorbol myristate acetate; PMA-THP1, PMA-differentiated THP1; PMs: peritoneal macrophages; PTMs: posttranslational modifications; RBR: RING1-IBR-RING2; RNF144A: ring finger protein 144A; STING1, stimulator of interferon response cGAMP interactor 1; TBK1, TANK binding kinase 1; TNF/TNF-α: tumor necrosis factor.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"789-806"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752341","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":"Survival strategies of cancer cells: the role of macropinocytosis in nutrient acquisition, metabolic reprogramming, and therapeutic targeting.","authors":"Guoshuai Xu, Qinghong Zhang, Renjia Cheng, Jun Qu, Wenqiang Li","doi":"10.1080/15548627.2025.2452149","DOIUrl":"10.1080/15548627.2025.2452149","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Macropinocytosis is a nonselective form of endocytosis that allows cancer cells to largely take up the extracellular fluid and its contents, including nutrients, growth factors, etc. We first elaborate meticulously on the process of macropinocytosis. Only by thoroughly understanding this entire process can we devise targeted strategies against it. We then focus on the central role of the MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) in regulating macropinocytosis, highlighting its significance as a key signaling hub where various pathways converge to control nutrient uptake and metabolic processes. The article covers a comprehensive analysis of the literature on the molecular mechanisms governing macropinocytosis, including the initiation, maturation, and recycling of macropinosomes, with an emphasis on how these processes are hijacked by cancer cells to sustain their growth. Key discussions include the potential therapeutic strategies targeting macropinocytosis, such as enhancing drug delivery via this pathway, inhibiting macropinocytosis to starve cancer cells, blocking the degradation and recycling of macropinosomes, and inducing methuosis - a form of cell death triggered by excessive macropinocytosis. Targeting macropinocytosis represents a novel and innovative approach that could significantly advance the treatment of cancers that rely on this pathway for survival. Through continuous research and innovation, we look forward to developing more effective and safer anti-cancer therapies that will bring new hope to patients.&lt;b&gt;Abbreviation&lt;/b&gt;: AMPK: AMP-activated protein kinase; ASOs: antisense oligonucleotides; CAD: carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase; DC: dendritic cell; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; ERBB2: erb-b2 receptor tyrosine kinase 2; ESCRT: endosomal sorting complex required for transport; GAP: GTPase-activating protein; GEF: guanine nucleotide exchange factor; GRB2: growth factor receptor bound protein 2; LPP: lipopolyplex; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; NSCLC: non-small cell lung cancer; PADC: pancreatic ductal adenocarcinoma; PDPK1: 3-phosphoinositide dependent protein kinase 1; PI3K: phosphoinositide 3-kinase; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns(3,4,5)P&lt;sub&gt;3&lt;/sub&gt;: phosphatidylinositol-(3,4,5)-trisphosphate; PtdIns(4,5)P&lt;sub&gt;2&lt;/sub&gt;: phosphatidylinositol-(4,5)-bisphosphate; PTT: photothermal therapies; RAC1: Rac family small GTPase 1; RPS6: ribosomal protein S6; RPS6KB1: ribosomal protein S6 kinase B1; RTKs: receptor tyrosine kinases; SREBF: sterol regulatory element binding transcription factor; TFEB: transcription factor EB; TNBC: triple-negative breast cancer; TSC2: TSC complex subunit 2; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-prot","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"693-718"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018075","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":"TBK1 is a signaling hub in coordinating stress-adaptive mechanisms in head and neck cancer progression.","authors":"Hyo Jeong Kim, Haeng-Jun Kim, Sun-Yong Kim, Jin Roh, Ju Hyun Yun, Chul-Ho Kim","doi":"10.1080/15548627.2025.2481661","DOIUrl":"10.1080/15548627.2025.2481661","url":null,"abstract":"<p><p>Tumorigenesis is closely linked to the ability of cancer cells to activate stress-adaptive mechanisms in response to various cellular stressors. Stress granules (SGs) play a crucial role in promoting cancer cell survival, invasion, and treatment resistance, and influence tumor immune escape by protecting essential mRNAs involved in cell metabolism, signaling, and stress responses. TBK1 (TANK binding kinase 1) functions in antiviral innate immunity, cell survival, and proliferation in both the tumor microenvironment and tumor cells. Here, we report that MUL1 loss results in the hyperactivation of TBK1 in both HNC cells and tissues. Mechanistically, under proteotoxic stress induced by proteasomal inhibition, HSP90 inhibition, or Ub⁺ stress, MUL1 promotes the degradation of active TBK1 through K48-linked ubiquitination at lysine 584. Furthermore, TBK1 facilitates autophagosome-lysosome fusion and phosphorylates SQSTM1, regulating selective macroautophagic/autophagic clearance in HNC cells. TBK1 is required for SG formation and cellular protection. Moreover, we found that MAP1LC3B is partially localized within SGs. TBK1 depletion enhances the sensitivity of HNC cells to cisplatin-induced cell death. GSK8612, a novel TBK1 inhibitor, significantly inhibits HNC tumorigenesis in xenografts. In summary, our study reveals that TBK1 facilitates the rapid removal of ubiquitinated proteins within the cell through protective autophagy under stress conditions and assists SG formation through the use of the autophagy machinery. These findings highlight the potential of TBK1 as a therapeutic target in HNC treatment.<b>Abbreviations</b>: ALP: autophagy-lysosomal pathway; AMBRA1: autophagy and beclin 1 regulator 1; BaF: bafilomycin A₁; CC: coiled-coil; CD274/PDL-1: CD274 molecule; CHX: cycloheximide; CQ: chloroquine; DNP: dinitrophenol; EGFR: epidermal growth factor receptor; ESCC: esophageal squamous cell carcinoma; G3BP1: G3BP stress granule assembly factor 1; HNC: head and neck cancer; HPV: human papillomavirus; IFN: interferon; IGFBP3: insulin like growth factor binding protein 3; IRF: interferon-regulatory factor 3; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; NPC: nasopharyngeal carcinoma; PABP: poly(A) binding protein; PI: proteasome inhibitor; PQC: protein quality control; PROTAC: proteolysis-targeting chimera; PURA/PURα: purine rich element binding protein A; RIGI: RNA sensor RIG-I; SD: standard deviation; SG: stress granule; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; UPS: ubiquitin-proteasome system; USP10: ubiquitin specific peptidase 10; VCP: valosin containing protein; VHL: von Hippel-Lindau tumor suppressor; WT: wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-23"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671920","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":"910-911"},"PeriodicalIF":0.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901034","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}