Autophagy最新文献

{"title":"Inhibition of PINK1 senses ROS signaling to facilitate neuroblastoma cell pyroptosis.","authors":"Yuyuan Zhu, Min Cao, Yancheng Tang, Yifan Liu, Haiji Wang, Jiaqi Qi, Cainian Huang, Chenghao Yan, Xu Liu, Sijia Jiang, Yufei Luo, Shaogui Wang, Bo Zhou, Haodong Xu, Ying-Ying Lu, Liming Wang","doi":"10.1080/15548627.2025.2487037","DOIUrl":"10.1080/15548627.2025.2487037","url":null,"abstract":"<p><p>Mitochondria serve as the primary source of intracellular reactive oxygen species (ROS), which play a critical role in orchestrating cell death pathways such as pyroptosis in various types of cancers. PINK1-mediated mitophagy effectively removes damaged mitochondria and reduces detrimental ROS levels, thereby promoting cell survival. However, the regulation of pyroptosis by PINK1 and ROS in neuroblastoma remains unclear. In this study, we demonstrate that inhibition or deficiency of PINK1 sensitizes ROS signaling and promotes pyroptosis in neuroblastoma cells via the BAX-caspase-GSDME signaling pathway. Specifically, inhibition of PINK1 by AC220 or knockout of <i>PINK1</i> impairs mitophagy and enhances ROS production, leading to oxidation and oligomerization of TOMM20, followed by mitochondrial recruitment and activation of BAX. Activated BAX facilitates the release of CYCS (cytochrome c, somatic) from the mitochondria into the cytosol, activating CASP3 (caspase 3). Subsequently, activated CASP3 cleaves and activates GSDME, inducing pyroptosis. Furthermore, inhibition or deficiency of PINK1 potentiates the anti-tumor effects of the clinical ROS-inducing drug ethacrynic acid (EA) to inhibit neuroblastoma progression <i>in vivo</i>. Therefore, our study provides a promising intervention strategy for neuroblastoma through the induction of pyroptosis.<b>Abbreviation:</b> AC220, quizartinib; ANOVA, analysis of variance; ANXA5, annexin A5; BAX, BCL2 associated X, apoptosis regulator; BAK1, BCL2 antagonist/killer 1; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; COX4/COX IV, cytochrome c oxidase subunit 4; CS, citrate synthase; CSC, cancer stem cell; CYCS, cytochrome c, somatic; DTT, dithiothreitol; DNA, deoxyribonucleic acid; EA, ethacrynic acid; Fer-1, ferroptosis inhibitor ferrostatin-1; FLT3, fms related tyrosine kinase 3; GSDMD, gasdermin D; GSDME, gasdermin E; kDa, kilodalton; LDH, lactate dehydrogenase; MFN1, mitofusin 1; MFN2, mitofusin 2; mito, mitochondria; mito-ROS, mitochondrial ROS; mtKeima, mitochondria-targeted monomeric keima-red; ml, microliter; MT-CO2, mitochondrially encoded cytochrome c oxidase II; NAC, antioxidant N-acetyl-L-cysteine; Nec-1, necroptosis inhibitor necrostatin-1; OMA1, OMA1 zinc metallopeptidase; OMM, outer mitochondrial membrane; PARP, poly(ADP-ribose) polymerase; PBS, phosphate-buffered saline; PI, propidium iodide; PINK1, PTEN induced kinase 1; PRKN/Parkin, parkin RBR E3 ubiquitin protein ligase; Q-VD, Q-VD-OPH; ROS, reactive oxygen species; sg, single guide; sh, short hairpin; STS, staurosporine; TOMM20, translocase of outer mitochondrial membrane 20; TIMM23, translocase of inner mitochondrial membrane 23; μm, micrometer; μM, micromolar.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2091-2110"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756516","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":"The structure-function relationship of ATE1 R-transferase of the autophagic Arg/N-degron pathway.","authors":"Su Bin Kim, Ji Su Lee, Xin Lan, Wei Huang, Derek J Taylor, Yong Tae Kwon, Yi Zhang, Chang Hoon Ji","doi":"10.1080/15548627.2025.2473393","DOIUrl":"10.1080/15548627.2025.2473393","url":null,"abstract":"<p><p>ATE1 (arginyltransferase 1; EC 2.3.2) transfers the amino acid arginine (Arg) from Arg-tRNA^Arg to the N-terminal (Nt) residues of proteins, such as aspartate (Asp), glutamate (Glu), and oxidized cysteine (Cys). The resulting Nt-Arg acts as an N-degron that regulates the degradation of various biomaterials via the ubiquitin/Ub-proteasome system (UPS) or the autophagy-lysosome system (ALS). In the UPS, Arg/N-degrons are recognized by cognate N-recognins, leading to substrate ubiquitination and proteasomal degradation. In the ALS, the same degrons bind the macroautophagy/autophagy receptor SQSTM1/p62 (sequestosome 1) to facilitate self-polymerization of SQSTM1 associated with cargoes and SQSTM1 interaction with LC3-II on phagophores. A key unresolved question is why only a small subset of proteins acquires Arg/N-degrons, given the rather weak binding affinity of ATE1 for Nt-substrates. In this study, we determined the cryo-EM structures of human ATE1 in complex with Arg-tRNA^Arg and an Nt-Asp peptide. ATE1 harbors two adjacent pockets that each bind an Nt-substrate or Arg-tRNA^Arg, the latter being wrapped by a long, unstructured loop. In the apo state, two ATE1 monomers form a homodimer. ATE1 achieves the selectivity for its peptidyl-ligands through these multivalent interactions, with K_d values in the micro-molar range. These results reveal the structural principle of Nt-arginylation at the crossroads of the UPS and ALS.<b>Abbreviations</b>: ALS: autophagy-lysosome system; Arg: arginine; Asp: aspartate; ATE1: arginyltransferase 1; Cys: cysteine; CysO₂(H): Cys sulfinic acid; Glu: glutamate; Nt: N-terminal; UBR: ubiquitin protein ligase E3 component n-recognin; UPS: ubiquitin-proteasome system; ZZ: ZZ-type zinc finger.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2293-2295"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143660095","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":"ATP2A2 regulates STING1/MITA-driven signal transduction including selective autophagy.","authors":"Xue Yang, Linyue Lv, Yuelan Zhang, Zhuyou Zhang, Shaowei Zeng, Xinyi Zhang, Qinyang Wang, Martin Dorf, Shitao Li, Bishi Fu","doi":"10.1080/15548627.2025.2496786","DOIUrl":"10.1080/15548627.2025.2496786","url":null,"abstract":"<p><p>STING1/MITA not only induces innate immune responses but also triggers macroautophagy/autophagy to selectively degrade signaling molecules. However, the molecular mechanisms regulating STING1-mediated selective autophagy remain unclear. Here, we first report that ATP2A2 directly interacts with STING1, regulating STING1-mediated innate immune response by modulating its polymerization and trafficking, thereby inhibiting DNA virus infection. Notably, while screening for reticulophagy receptors involved in STING1-mediated selective autophagy, we identified SEC62 as an important receptor protein in STING1-mediated reticulophagy. Mechanistically, SEC62 strengthens its interaction with STING1 upon activation and concurrently facilitates STING1-mediated reticulophagy upon starvation, which are dependent on ATP2A2. Furthermore, knocking down SEC62 in WT cells inhibits STING1-mediated MAP1LC3B/LC3B lipidation and autophagosome formation, an effect that is lost in <i>ATP2A2</i> knockout cells, suggesting that SEC62's role in STING1-mediated selective autophagy is ATP2A2 dependent. Thus, our findings identify the reticulophagy receptor SEC62 as a novel receptor protein regulating STING1-mediated selective autophagy, providing new insight into the mechanism regarding a reticulophagy receptor in the process of STING1-induced selective autophagy.<b>Abbrevations:</b> aa: amino acids; AP-MS: affinity tag purification-mass spectrometry; ATP2A1: ATPase sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting 1; ATP2A2: ATPase sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting 2; ATP2A3: ATPase sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting 3; CANX: calnexin; CCPG1: cell cycle progression 1; CGAS: cyclic GMP-AMP synthase; ctDNA: calf thymus DNA; dsRNA: double-stranded RNA; diABZI: diamidobenzimidazole; ER: endoplasmic reticulum; ERGIC: ER-Golgi intermediate compartment; EBSS: Earle's Balanced Salt Solution; EV: empty vector; FL: full length; GOLGA2/GM130: golgin A2; HSV-1: herpes simplex virus type 1; IRF3: interferon regulatory factor 3; IFNs: type I interferons; ISD: interferon stimulatory DNA; KO: knockout; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; poly(I:C): polyinosinic-polycytidylic acid; NBR1: NBR1 autophagy cargo receptor; PRR: pattern recognition receptor; reticulophagy: selective autophagic degradation of the ER; RETREG1/FAM134B: reticulophagy regulator 1; RIGI: RNA sensor RIG-I; RTN3L: reticulon 3; SEC62: SEC62 homolog, preprotein translocation factor; SeV: Sendai virus; STIM1: stromal interaction molecule 1; STING1/MITA: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TEX264: testis expressed 264, ER-phagy receptor; TMX1: thioredoxin related transmembrane protein 1; VSV: vesicular stomatitis virus; VACV: vaccinia virus; ZMPSTE24: zinc metallopeptidase STE24.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2230-2245"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053588","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":"NAD⁺ repletion restores cardioprotective autophagy and mitophagy in obesity-associated heart failure by suppressing excessive trophic signaling.","authors":"Mahmoud Abdellatif, Francisco Vasques-Nóvoa, João Pedro Ferreira, Junichi Sadoshima, Abhinav Diwan, Wolfgang A Linke, Guido Kroemer, Simon Sedej","doi":"10.1080/15548627.2025.2522127","DOIUrl":"10.1080/15548627.2025.2522127","url":null,"abstract":"<p><p>Macroautophagy/autophagy is markedly inhibited in the hearts of elderly obese patients with heart failure and preserved ejection fraction (HFpEF). However, the therapeutic relevance and underlying signaling mechanisms of the decline of autophagy in HFpEF remain unclear. We observed that therapeutic nicotinamide adenine dinucleotide (NAD⁺) repletion via nicotinamide supplementation restores cardioprotective autophagy and mitophagy in preclinical models of obesity-related HFpEF. Targeted and untargeted cardiac acetylome profiling revealed no significant deacetylation of essential autophagy-related proteins, including ATG5, ATG7 and mammalian Atg8-family members (ATG8s), suggesting a SIRT (sirtuin)-independent mechanism of autophagy induction by nicotinamide. Instead, cardiac transcriptomic analysis revealed major shifts in insulin-IGF1 (insulin-like growth factor 1) signaling, a known autophagy inhibitory pathway. Nicotinamide supplementation reverses the HFpEF-associated increase in insulin-IGF1 signaling, whereas exogenous IGF1 counteracts nicotinamide-induced autophagy. Importantly, nicotinamide fails to exert cardioprotective effects in mice lacking the autophagy-related protein ATG5 in cardiomyocytes, implicating autophagy as essential for the therapeutic response. In patients with HFpEF, a metabolic shift diverting nicotinamide away from NAD⁺ biosynthesis toward catabolism strongly correlates with worsening heart failure and increased cardiovascular mortality, even after adjusting for traditional risk factors. In sum, we demonstrate that NAD⁺ replenishment improves cardiometabolic HFpEF by restoring cardiac autophagy through suppression of excessive IGF1 signaling.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2296-2298"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144487439","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":"Lysosomal membrane permeabilization enhances the anticancer effects of POLR1 (RNA polymerase I) transcription inhibitors.","authors":"Lucille Ferret, Jonathan G Pol, Allan Sauvat, Gautier Stoll, Karla Alvarez-Valadez, Alexandra Muller, Julie Le Naour, Felix Peyre, Gerasimos Anagnostopoulos, Isabelle Martins, Maria Chiara Maiuri, Harald Wodrich, Lionel Guittat, Jean-Louis Mergny, Guido Kroemer, Mojgan Djavaheri-Mergny","doi":"10.1080/15548627.2025.2497614","DOIUrl":"10.1080/15548627.2025.2497614","url":null,"abstract":"<p><p>Lysosomes contribute to the development of drug resistance through various mechanisms that include drug sequestration and the activation of adaptive stress pathways. While inhibitors of DNA-to-RNA transcription exhibit potent anticancer effects, the role of lysosomes in modulating responses to such transcription inhibitors remains largely unexplored. This study investigates this aspect in the context of two potent POLR1 (RNA polymerase I) transcription inhibitors, CX-3543 (quarfloxin) and CX-5461 (pidnarulex). Unexpectedly, CX-3543 was found to accumulate within lysosomes, leading to lysosomal membrane permeabilization (LMP) and the subsequent activation of cellular stress adaptation pathways, including those regulated by the transcription factor TFEB and autophagy. Disrupting TFEB or autophagy increased cell sensitivity to CX-3543, highlighting the cytoprotective role of these processes in counteracting CX-3543-induced cell death. Moreover, targeting lysosomal membranes with chloroquine derivatives or blue light exposure induced substantial LMP, releasing compound CX-3543 from lysosomes. This effect enhanced both the inhibition of DNA-to-RNA transcription and CX-3543-induced cell death. Similar effects were observed when chloroquine derivatives were combined with CX-5461. Additionally, combining CX-3543 with the chloroquine derivative DC661 more effectively reduced the fibrosarcoma growth in immunocompetent mice than either agent alone. Altogether, our results reveal an unanticipated lysosome-related mechanism that contributes to cancer cell resistance to POLR1 inhibitors and propose a strategy to overcome this resistance.<b>Abbreviations</b>: ATG7: autophagy related 7; ATG13: autophagy related 13; Baf A₁: bafilomycin A₁; CTSB: cathepsin B; DKO: double knockout; G4: Guanine quadruplex; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LGALS3: galectin 3; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTORC1: mechanistic target of rapamycin kinase complex 1; NCL: nucleolin; POLR1: RNA polymerase I; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TFE3: transcription factor E3; ULK1: unc-51 like autophagy activating kinase 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2246-2265"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144318946","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":"PDZD8 links organelle crosstalk to synaptic remodeling via autophagy.","authors":"Rajan S Thakur, Kate M O'Connor-Giles","doi":"10.1080/15548627.2025.2537983","DOIUrl":"10.1080/15548627.2025.2537983","url":null,"abstract":"<p><p>Synapse formation and plasticity require coordinating cellular processes from signaling to protein turnover over long distances, placing high demands on intracellular communication. Membrane contact sites (MCSs) between organelles are specialized compartments for coordinating cellular processes, yet their functions in the developing nervous system remain poorly understood. Through an <i>in vivo</i> CRISPR screen in <i>Drosophila</i>, we identified the conserved endoplasmic reticulum (ER) MCS tethering protein Pdzd8 as a regulator of activity-dependent synapse development. Our <i>in vivo</i> studies demonstrate that Pdzd8 functions at ER-late endosome/lysosome MCSs to promote lysosomal maturation and increase autophagic flux during periods of high demand such as prolonged neuronal activity.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2299-2300"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777191","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":"Correction.","authors":"","doi":"10.1080/15548627.2024.2416687","DOIUrl":"10.1080/15548627.2024.2416687","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"xii-xiv"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514549","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":"METTL3-dependent m⁶A modification of SNAP29 induces \"autophagy-mitochondrial crisis\" in the ischemic microenvironment after soft tissue transplantation.","authors":"Ningning Yang, Yingying Lai, Gaoxiang Yu, Xuzi Zhang, Jingwei Shi, Linyi Xiang, Jiacheng Zhang, Yuzhe Wu, Xiaoqiong Jiang, Xuanlong Zhang, Liangliang Yang, Weiyang Gao, Jian Ding, Xiangyang Wang, Jian Xiao, Kailiang Zhou","doi":"10.1080/15548627.2025.2493455","DOIUrl":"10.1080/15548627.2025.2493455","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Necrosis at the ischemic distal end of flap transplants increases patients' pain and economic burden. Reactive oxygen species (ROS) and mitochondrial damage are crucial in regulating parthanatos, but the mechanisms linking disrupted macroautophagic/autophagic flux to parthanatos in ischemic flaps remain unclear. The results of western blotting, immunofluorescence staining, and a proteomic analysis revealed that the autophagic protein SNAP29 was deficient in ischemic flaps, resulting in disrupted autophagic flux, increased ROS-induced parthanatos, and aggravated ischemic flap necrosis. The use of AAV vector to restore SNAP29 &lt;i&gt;in vivo&lt;/i&gt; mitigated the disruption of autophagic flux and parthanatos. Additionally, quantification of the total m&lt;sup&gt;6&lt;/sup&gt;A level and RIP-qPCR, MeRIP-qPCR, and RNA stability assessments were performed to determine differential &lt;i&gt;Snap29&lt;/i&gt; mRNA m&lt;sup&gt;6&lt;/sup&gt;A methylation levels and mRNA stability in ischemic flaps. Various &lt;i&gt;in vitro&lt;/i&gt; and &lt;i&gt;in vivo&lt;/i&gt; tests were conducted to verify the ability of METTL3-mediated m&lt;sup&gt;6&lt;/sup&gt;A methylation to promote SNAP29 depletion and disrupt autophagic flux. Finally, we concluded that restoring SNAP29 by inhibiting METTL3 and YTHDF2 reversed the \"autophagy-mitochondrial crisis\", defined for the first time as disrupted autophagic flux, mitochondrial damage, mitochondrial protein leakage, and the occurrence of parthanatos. The reversal of this crisis ultimately promoted the survival of ischemic flaps.&lt;b&gt;Abbreviations&lt;/b&gt;: AAV = adeno-associated virus; ACTA2/α-SMA = actin alpha 2, smooth muscle, aorta; AIFM/AIF = apoptosis-inducing factor, mitochondrion-associated; ALKBH5 = alkB homolog, RNA demythelase; Baf A1 = bafilomycin A&lt;sub&gt;1&lt;/sub&gt;; CQ = chloroquine; DHE = dihydroethidium; ECs = endothelial cells; F-CHP = 5-FAM-conjugated collagen-hybridizing peptide; GO = gene ontology; HUVECs = human umbilical vein endothelial cells; KEGG = Kyoto Encyclopedia of Genes and Genomes; LC-MS/MS = liquid chromatography-tandem mass spectrometry; LDBF = laser doppler blood flow; m&lt;sup&gt;6&lt;/sup&gt;A = N6-methyladenosine; MAP1LC3/LC3 = microtubule-associated protein 1 light chain 3; MeRIP = methylated RNA immunoprecipitation; METTL3 = methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit; NAC = N-acetylcysteine; OGD = oxygen glucose deprivation; PAR = poly (ADP-ribose); PARP1 = poly (ADP-ribose) polymerase family, member 1; PECAM1/CD31 = platelet/endothelial cell adhesion molecule 1; ROS = reactive oxygen species; RT-qPCR = reverse transcription quantitative polymerase chain reaction; RIP = RNA immunoprecipitation; SNAP29 = synaptosomal-associated protein 29; SNARE = soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1 = sequestosome 1; SRAMP = sequence-based RNA adenosine methylation site predicting; STX17 = syntaxin 17; TMT = tandem mass tag; TUNEL = terminal deoxynucleotidyl transferase dUTP nick end labeling; VAMP8 = vesicle-associated membra","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2168-2191"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055272","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":"Pathological aging is alleviated by neutralization of the autophagy-repressive tissue hormone DBI/ACBP.","authors":"Léa Montégut, Flavia Lambertucci, Lucas Moledo-Nodar, Isabelle Martins, Alejandro Lucia, Clea Barcena, Guido Kroemer","doi":"10.1080/15548627.2025.2549451","DOIUrl":"10.1080/15548627.2025.2549451","url":null,"abstract":"<p><p>DBI/ACBP (diazepam binding inhibitor, acyl CoA-binding protein) is a macroautophagy/autophagy-inhibitory tissue hormone produced by multiple cell types. The plasma levels of DBI/ACBP rise with age and disease. In centenarians living in nursing homes, DBI/ACBP concentrations are approximately threefold higher than in younger adults (30-48 years old), but these levels increase further in centenarians hospitalized due to disease exacerbation. Elevated DBI/ACBP correlates with unfavorable clinical parameters, including high Charlson Comorbidity Index, elevated neutrophil:lymphocyte ratio, and decreased renal function. In mouse models, neutralization of DBI/ACBP using monoclonal antibodies ameliorates several aging-related pathologies. In <i>zmpste24</i>^<i>-/-</i> progeroid mice, anti-DBI/ACBP therapy improves posture, mobility, cutaneous and dental abnormalities, splenic atrophy, kidney function, and blood parameters. In models of renal aging induced by cisplatin or doxorubicin, DBI/ACBP neutralization suppresses renal fibrosis and cellular senescence. Similarly, in cardiac and hepatic aging models, anti-DBI/ACBP reduces expression of the senescence marker CDKN1A/p21 (cyclin dependent kinase inhibitor 1A) in cardiomyocytes and hepatocytes. Single-nucleus RNA sequencing of heart tissue revealed that anti-DBI/ACBP restores key metabolic and cardioprotective gene expression patterns suppressed by doxorubicin. Together, these findings establish DBI/ACBP as a marker and driver of pathological aging and demonstrate that its neutralization confers multi-organ anti-senescence effects. Thus, DBI/ACBP-targeting strategies hold therapeutic potential for improving healthspan.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2304-2306"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12459365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884447","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":"AlphaFold2 SLiM screen for LC3-LIR interactions in autophagy.","authors":"Jan Felix Maximilian Stuke, Gerhard Hummer","doi":"10.1080/15548627.2025.2493999","DOIUrl":"10.1080/15548627.2025.2493999","url":null,"abstract":"&lt;p&gt;&lt;p&gt;In selective macroautophagy/autophagy, cargo recruitment is mediated by MAP1LC3/LC3-interacting regions (LIRs)/Atg8-family interacting motifs (AIMs) in the cargo or cargo receptor proteins. The binding of these motifs to LC3/Atg8 proteins at the phagophore membrane is often modulated by post-translational modifications, especially phosphorylation. As a challenge for computational LIR predictions, sequences may contain the short canonical (W/F/Y)XX(L/I/V) motif without being functional. Conversely, LIRs may be formed by non-canonical but functional sequence motifs. AlphaFold2 has proven to be useful for LIR predictions, even if some LIRs are missed and proteins with thousands of residues reach the limits of computational feasibility. We present a fragment-based approach to address these limitations. We find that fragment length and phosphomimetic mutations modulate the interactions predicted by AlphaFold2. Systematic fragment screening for a range of target proteins yields structural models for interactions that AlphaFold2 and AlphaFold3 fail to predict for full-length targets. We provide guidance on fragment choice, sequence tuning, LC3 isoform effects, and scoring for optimal LIR screens. Finally, we also test the transferability of this general framework to SUMO-SIM interactions, another type of protein-protein interaction involving short linear motifs (SLiMs).&lt;b&gt;Abbreviations&lt;/b&gt;: 2-HP-LIR: ncLIR binding either or both HPs with non-canonical residues; AIM: Atg8-family interacting motif; ap. LIR: antiparallel LIR; &lt;i&gt;A.t&lt;/i&gt;.; &lt;i&gt;Arabidopsis thaliana&lt;/i&gt;; AT5G06830/C53 (&lt;i&gt;A.t&lt;/i&gt;.): CDK5RAP3-like protein; Atg8/ATG8: autophagy related 8, in yeast and plants, respectively; ATG8CL: ATG8C-like of &lt;i&gt;Solanum tuberosum&lt;/i&gt; (potato); ATG8E: ATG8e of &lt;i&gt;A.t&lt;/i&gt;.; Av. num. of contacts: average number of heavy atom contacts; BCL2: BCL2 apoptosis regulator; BNIP3: BCL2 interacting protein 3; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CALR: calreticulin; can. LIR: canonical LIR; CDF: cumulative distribution function; CDK5RAP3/C53 (&lt;i&gt;H.s&lt;/i&gt;.): CDK5 regulatory subunit associated protein 3; [DE]W[DE]-LIR: TRIM5-like ncLIR; DSK2A: ubiquitin domain-containing protein DSK2a; FUNDC1: FUN14 domain containing 1; GABARAP: GABA type A receptor-associated protein; HP0/1/2: hydrophobic pocket 0/1/2; HP0-LIR: ncLIR engaging HP0; &lt;i&gt;H.s&lt;/i&gt;.; &lt;i&gt;Homo sapiens&lt;/i&gt;; lcLIR: low-confidence LIR (ncLIR not similar to previously characterized ncLIRs); LDS: LIR-docking site; LIR: LC3-interacting region; LO score: length-weighted fraction of occurrence score; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MD: molecular dynamics; MEFV/pyrin: MEFV innate immunity regulator, pyrin; minPAE: minimum PAE; MSA: multiple sequence alignment; ncLIR: non-canonical LIR; NPC: nuclear pore complex; Nup159: nucleoporin 159; NUP214: nucleoporin 214; OPTN: optineurin; other@LDS: other interact","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"2192-2212"},"PeriodicalIF":14.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060841","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}