Autophagy最新文献

{"title":"Nuclear proteasomes as a backup for autophagy: interconnected proteostasis pathways.","authors":"Meiyan Jin, Daniel J Klionsky","doi":"10.1080/15548627.2024.2416261","DOIUrl":"https://doi.org/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":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482859","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":"Copper aggravated synaptic damage after traumatic brain injury by downregulating BNIP3-mediated mitophagy.","authors":"Hanxiao Chang, Weiwei Zhang, Lei Xu, Zheng Li, Chao Lin, Yuqi Shen, Guangjian Zhang, Lei Mao, Chencheng Ma, Ning Liu, Hua Lu","doi":"10.1080/15548627.2024.2409613","DOIUrl":"https://doi.org/10.1080/15548627.2024.2409613","url":null,"abstract":"<p><p>Synaptic damage is a crucial pathological process in traumatic brain injury. However, the mechanisms driving this process remain poorly understood. In this report, we demonstrate that the accumulation of damaged mitochondria, resulting from impaired mitphagy, plays a significant role in causing synaptic damage. Moreover, copper induced downregulation of BNIP3 is a key player in regulating mitophagy. DMSA alleviates synaptic damage and mitochondrial dysfunction by promoting urinary excretion of copper. Mechanistically, we find that copper downregulate BNIP3 by increasing the nuclear translocation of NFKB, which is triggered by TRIM25-mediated ubiquitination-dependent degradation of NFKBIA. Our study underscores the importance of copper accumulation in the regulation of BNIP3-mediated mitophagy and suggests that therapeutic targeting of the copper-TRIM25-NFKB-BNIP3 axis holds promise to attenuate synaptic damage after traumatic brain injury.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482855","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":"https://doi.org/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":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2024-10-14","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":"Interactors and neighbors of ULK1 complex members.","authors":"Devanarayanan Siva Sankar, Joern Dengjel","doi":"10.1080/15548627.2024.2414386","DOIUrl":"https://doi.org/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":"1-3"},"PeriodicalIF":0.0,"publicationDate":"2024-10-14","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":"SMURF1 mediates damaged lysosomal homeostasis by ubiquitinating PPP3CB to promote the activation of TFEB.","authors":"Qin Xia, Xuan Liu, Lu Zhong, Jun Qu, Lei Dong","doi":"10.1080/15548627.2024.2407709","DOIUrl":"10.1080/15548627.2024.2407709","url":null,"abstract":"<p><p>The calcium-activated phosphatase PPP3/calcineurin dephosphorylates TFEB (transcription factor EB) to trigger its nuclear translocation and the activation of macroautophagic/autophagic targets. However, the detailed molecular mechanism regulating TFEB activation remains poorly understood. Here, we highlighted the importance of SMURF1 (SMAD specific E3 ubiquitin protein ligase 1) in the activation of TFEB for lysosomal homeostasis. SMURF1 deficiency prevents the calcium-triggered ubiquitination of the catalytic subunit of PPP3/calcineurin in a manner consistent with defective autophagic degradation of damaged lysosomes. Mechanically, PPP3CB/CNA2 plays a bridging role in the recruitment of SMURF1 by LGALS3 (galectin 3) upon lysosome damage. Importantly, PPP3CB increases the dissociation of the N-terminal tail (NT) and C-terminal carbohydrate-recognition domain (CRD) of LGALS3, which may promote the formation of open conformers in a PPP3CB dephosphorylation activity-dependent manner. In addition, PPP3CB is ubiquitinated at lysine 146 by the recruited SMURF1 in response to intracellular calcium stimulation. The K63-linked ubiquitination of PPP3CB enhances the recruitment of TFEB. Moreover, TFEB directly interacts with both PPP3CB and the regulatory subunit PPP3R1 which facilitate the conformational correction of TFEB for its activation for the transcription of TFEB-targeted genes. Altogether, our results highlighted a critical mechanism for the regulation of PPP3/calcineurin activity via its ubiquitin ligase SMURF1 in response to lysosomal membrane damage, which may account for a potential target for the treatment of stress-related diseases.<b>Abbreviation</b> AID: autoinhibitory domain; ATG: autophagy related; CD: catalytic domain; CRD: carbohydrate-recognition domain; CsA: cyclosporin A; DMSO: dimethyl sulfoxide; ESCRT: endosomal sorting complexes required for transport; GSK3B: glycogen synthase kinase 3 beta; LAMP1: lysosomal associated membrane protein 1; LGALS3: galectin 3; LLOMe: L-leucyl-L-leucine methyl ester; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; ML-SA1: mucolipin synthetic agonist 1; MTORC1: mechanistic target of rapamycin kinase complex 1; NT: N-terminal tail; PPP3CB: protein phosphatase 3 catalytic subunit beta; PPP3R1: protein phosphatase 3 regulatory subunit B, alpha; SMURF1: SMAD specific E3 ubiquitin protein ligase 1; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; VCP/p97: valosin containing protein; YWHA/14-3-3: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-18"},"PeriodicalIF":0.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334260","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":"Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules.","authors":"Sho Matsui, Takeshi Yamamoto, Yoshitsugu Takabatake, Atsushi Takahashi, Tomoko Namba-Hamano, Jun Matsuda, Satoshi Minami, Shinsuke Sakai, Hiroaki Yonishi, Jun Nakamura, Shihomi Maeda, Ayumi Matsumoto, Isao Matsui, Motoko Yanagita, Yoshitaka Isaka","doi":"10.1080/15548627.2024.2410621","DOIUrl":"10.1080/15548627.2024.2410621","url":null,"abstract":"<p><p>The renoprotective effects of SLC5A2/SGLT2 (solute carrier 5 (sodium/glucose cotransporter), member 2) inhibitors have recently been demonstrated in non-diabetic chronic kidney disease (CKD), even without overt albuminuria. However, the mechanism underlying this renoprotection is largely unclear. We investigated the renoprotective mechanisms of the SLC5A2 inhibitor empagliflozin with a focus on ALB (albumin) reabsorption and macroautophagy/autophagy in proximal tubules using wild-type or drug-inducible <i>lrp2/Megalin</i> or <i>atg5</i> knockout mice with high-fat diet (HFD)-induced obesity or 5/6 nephrectomy that elevated intraglomerular pressure without overt albuminuria. Empagliflozin treatment of HFD-fed mice reduced several hallmarks of lipotoxicity in the proximal tubules, such as phospholipid accumulation in the lysosome, inflammation and fibrosis. Empagliflozin, which decreases intraglomerular pressure, not only reduced the HFD-induced increase in ALB reabsorption <i>via</i> LRP2 in the proximal tubules (<i>i.e</i>. total nephron ALB filtration), as assessed by urinary ALB excretion caused by genetic ablation of <i>Lrp2</i>, but also ameliorated the HFD-induced imbalance in circulating ALB-bound fatty acids. Empagliflozin alleviated the HFD-induced increase in autophagic demand and successfully prevented autophagic stagnation in the proximal tubules. Similarly, empagliflozin decreased ALB exposure and autophagic demand in 5/6 nephrectomized mice. Finally, empagliflozin reduced HFD-induced vulnerability to ischemia-reperfusion injury, whereas LRP2 blockade and <i>atg5</i> ablation separately diminished this effect. Our findings indicate that empagliflozin reduces ALB exposure and prevents autophagic stagnation in the proximal tubules even without overt albuminuria. Autophagy improvement may be critical for the renoprotection mediated by SLC5A2 inhibition.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-15"},"PeriodicalIF":0.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLC2 (clathrin light chain 2)-ATG8h/ATG8i interactions connect clathrin-mediated endocytosis (CME) and the autophagy pathway.","authors":"Hujiao Lan, Yating Zhao, Minjun Huang, Wenxu Wang, Jianzhong Liu","doi":"10.1080/15548627.2024.2414451","DOIUrl":"https://doi.org/10.1080/15548627.2024.2414451","url":null,"abstract":"<p><p>Extensive interconnection has been established between clathrin-mediated endocytosis (CME) and the macroautophagy/autophagy pathway in yeast and mammals. However, the evidence that connects these two pathways in plants has been limited. Starting from the phenotypic similarities in carbon starvation and immune responses shared between the double mutant of CLC2 (clathrin light chain 2) and <i>CLC3</i>, <i>clc2-1 clc3-1</i>, and the <i>atg2-1</i> mutant in Arabidopsis, we found that the autophagy pathway is compromised in the <i>clc2-1 clc3-1</i> mutant. Subsequently, we demonstrated that CLC2 interacts specifically with ATG8h and ATG8i, two clade II ATG8 isoforms. The CLC2-ATG8h/ATG8i interaction depends on an Atg8-family interacting motif (AIM) present in CLC2 and an AIMs docking site (ADS) present in ATG8h, respectively. In addition, CLC2-GFP is subjected to autophagic degradation and the degradation of GFP-ATG8h is significantly reduced in the <i>clc2-1 clc3-1</i> mutant. Last, simultaneously knocking out <i>ATG8h</i> and <i>ATG8i</i> enhances disease resistance, corroborating the functional relevance of the CLC2-ATG8h/8i interactions. These findings reveal that CME and the autophagy pathway are intersected via CLC2-ATG8h/8i interactions in Arabidopsis.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATP6V1D drives hepatocellular carcinoma stemness and progression via both lysosome acidification-dependent and -independent mechanisms.","authors":"Zhijie Xu, Ruiyang Liu, Haoying Ke, Fuyuan Xu, Pengfei Yang, Weiyu Zhang, Yi Zhan, Zhiju Zhao, Fei Xiao","doi":"10.1080/15548627.2024.2406186","DOIUrl":"10.1080/15548627.2024.2406186","url":null,"abstract":"<p><p>Metabolic reprogramming is pivotal in cancer stem cell (CSC) self-renewal. However, the intricate regulatory mechanisms governing the crosstalk between metabolic reprogramming and liver CSCs remain elusive. Here, using a metabolic CRISPR-Cas9 knockout screen, we identify ATP6V1D, a subunit of the vacuolar-type H⁺-translocating ATPase (V-ATPase), as a key metabolic regulator of hepatocellular carcinoma (HCC) stemness. Elevated ATP6V1D expression correlates with poor clinical outcomes in HCC patients. ATP6V1D knockdown inhibits HCC stemness and malignant progression both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, ATP6V1D enhances HCC stemness and progression by maintaining macroautophagic/autophagic flux. Specifically, ATP6V1D not only promotes lysosomal acidification, but also enhances the interaction between CHMP4B and IST1 to foster ESCRT-III complex assembly, thereby facilitating autophagosome-lysosome fusion to maintain autophagic flux. Moreover, silencing CHMP4B or IST1 attenuates HCC stemness and progression. Notably, low-dose bafilomycin A₁ targeting the V-ATPase complex shows promise as a potential therapeutic strategy for HCC. In conclusion, our study highlights the critical role of ATP6V1D in driving HCC stemness and progression via the autophagy-lysosomal pathway, providing novel therapeutic targets and approaches for HCC treatment.<b>Abbreviations:</b> 3-MA: 3-methyladenine; ANT: adjacent normal liver tissues; ATP6V1D: ATPase H+ transporting V1 subunit D; BafA1: bafilomycin A₁; CHMP: charged multivesicular body protein; co-IP: co-immunoprecipitation; CSC: cancer stem cell; ESCRT: endosomal sorting complex required for transport; HCC: hepatocellular carcinoma; IF: immunofluorescence; IHC: immunohistochemical; LCSCs: liver cancer stem cells; qRT-PCR: quantitative real time PCR; V-ATPase: vacuolar-type H⁺- translocating ATPase; WB: western blot.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":0.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334256","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":"Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in <i>Drosophila</i> and Vici syndrome patients.","authors":"Celine Deneubourg, Hormos Salimi Dafsari, Simon Lowe, Aitana Martinez-Cotrina, David Mazaud, Seo Hyun Park, Virginia Vergani, Amanda Almacellas Barbanoj, Reza Maroofian, Luisa Averdunk, Ehsan Ghayoor-Karimiani, Sandeep Jayawant, Cyril Mignot, Boris Keren, Renate Peters, Arveen Kamath, Lauren Mattas, Sumit Verma, Arpana Silwal, Felix Distelmaier, Henry Houlden, Gabriele Lignani, Adam Antebi, James Jepson, Heinz Jungbluth, Manolis Fanto","doi":"10.1080/15548627.2024.2405956","DOIUrl":"10.1080/15548627.2024.2405956","url":null,"abstract":"<p><p>Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 (<i>EPG5</i>) gene that is crucial for autophagosome-lysosome fusion and autophagic clearance. Here, we used <i>Drosophila melanogaster</i> to study the importance of Epg5 in development, aging, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with <i>Drosophila</i> predictions.<b>Abbreviations</b>: AD: Alzheimer's disease; ALS-FTD: Amyotrophic Lateral Sclerosis-FrontoTemoporal Dementia; DART: <i>Drosophila</i> Arousal Tracking; ECoG: electrocorticogram; EEG: electroencephalogram; <i>EPG5</i>: ectopic P-granules 5 autophagy tethering factor; KA: kainic acid; MBs: mushroom bodies; MRI magnetic resonance imaging; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson's disease; <i>TSC</i>: TSC complex; VS: Vici syndrome.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-13"},"PeriodicalIF":0.0,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334257","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":"Autophagy controls neuronal differentiation by regulating the WNT-DVL signaling pathway.","authors":"Vincencius Vidyawan, Lesly Puspita, Virginia Blessy Juwono, Magdalena Deline, Kelvin Pieknell, Mi-Yoon Chang, Sang-Hun Lee, Jae-Won Shim","doi":"10.1080/15548627.2024.2407707","DOIUrl":"10.1080/15548627.2024.2407707","url":null,"abstract":"<p><p>Macroautophagy/autophagy dysregulation is associated with various neurological diseases, including Vici syndrome. We aimed to determine the role of autophagy in early brain development. We generated neurons from human embryonic stem cells and developed a Vici syndrome model by introducing a loss-of-function mutation in the <i>EPG5</i> gene. Autophagy-related genes were upregulated at the neuronal progenitor cell stage. Inhibition of autolysosome formation with bafilomycin A₁ treatment at the neuronal progenitor cell stage delayed neuronal differentiation. Notably, WNT (Wnt family member) signaling may be part of the underlying mechanism, which is negatively regulated by autophagy-mediated DVL2 (disheveled segment polarity protein 2) degradation. Disruption of autolysosome formation may lead to failure in the downregulation of WNT signaling, delaying neuronal differentiation. <i>EPG5</i> mutations disturbed autolysosome formation, subsequently inducing defects in progenitor cell differentiation and cortical layer generation in organoids. Disrupted autophagy leads to smaller organoids, recapitulating Vici syndrome-associated microcephaly, and validating the disease relevance of our study.<b>Abbreviations</b>: BafA1: bafilomycin A1; co-IP: co-immunoprecipitation; DVL2: dishevelled segment polarity protein 2; EPG5: ectopic P-granules 5 autophagy tethering factor; gRNA, guide RNA; hESC: human embryonic stem cells; KO: knockout; mDA, midbrain dopamine; NIM: neural induction media; NPC: neuronal progenitor cell; qPCR: quantitative polymerase chain reaction; UPS: ubiquitin-proteasome system; WNT: Wnt family member; WT: wild type.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-18"},"PeriodicalIF":0.0,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395879","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}