Autophagy最新文献

{"title":"Deciphering melanophagy: role of the PTK2-ITCH-MLANA-OPTN cascade on melanophagy in melanocytes.","authors":"Na Yeon Park, Doo Sin Jo, Hyun Jun Park, Ji-Eun Bae, Yong Hwan Kim, Joon Bum Kim, Ha Jung Lee, Sung Hyun Kim, Hyunjung Choi, Hyun-Shik Lee, Tamotsu Yoshimori, Dong-Seok Lee, Jin-A Lee, Pansoo Kim, Dong-Hyung Cho","doi":"10.1080/15548627.2024.2421695","DOIUrl":"10.1080/15548627.2024.2421695","url":null,"abstract":"<p><p>Melanosomes play a pivotal role in skin color and photoprotection. In contrast to the well-elucidated pathway of melanosome biogenesis, the process of melanosome degradation, referred to as melanophagy, is largely unexplored. Previously, we discovered that 3,4,5-trimethoxycinnamate thymol ester (TCTE) effectively inhibits skin pigmentation by activating melanophagy. In this study, we discovered a new regulatory signaling cascade that controls melanophagy in TCTE-treated melanocytes. ITCH (itchy E3 ubiquitin protein ligase) facilitates ubiquitination of the melanosome membrane protein MLANA (melan-A) during TCTE-induced melanophagy. This ubiquitinated MLANA is then recognized by an autophagy receptor protein, OPTN (optineurin). Additionally, a phospho-kinase antibody array revealed that TCTE activates PTK2 (protein tyrosine kinase 2), which phosphorylates ITCH, enhancing the ubiquitination of MLANA. Furthermore, inhibition of either PTK2 or ITCH disrupts the ubiquitination of MLANA and the MLANA-OPTN interaction in TCTE-treated cells. Taken together, our findings highlight the critical role of the PTK2-ITCH-MLANA-OPTN cascade in orchestrating melanophagy progression.<b>Abbreviations</b>: α-MSH: alpha-melanocyte-stimulating hormone; dichlone: 2,3-dichloro-1,4-naphthoquinone; ITCH: itchy E3 ubiquitin protein ligase; MITF: melanocyte inducing transcription factor; MLANA: melan-A; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PINK1: PTEN induced kinase 1; PTK2: protein tyrosine kinase 2; SQSTM1/p62: sequestosome 1; TCTE: 3,4,5-trimethoxycinnamate thymol ester; TPC2: two pore segment channel 2; VDAC1: voltage dependent anion channel 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549513","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":"HSP90 N-terminal inhibition promotes mitochondria-derived vesicles related metastasis by reducing TFEB transcription via decreased HSP90AA1-HCFC1 interaction in liver cancer.","authors":"Lixia Liu, Zhenming Zheng, Yaling Huang, Hairou Su, Guibing Wu, Zihao Deng, Yan Li, Guantai Xie, Jieyou Li, Fei Zou, Xuemei Chen","doi":"10.1080/15548627.2024.2421703","DOIUrl":"10.1080/15548627.2024.2421703","url":null,"abstract":"<p><p>Cancer cells compensate with increasing mitochondria-derived vesicles (MDVs) to maintain mitochondrial homeostasis, when canonical MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta)-mediated mitophagy is lacking. MDVs promote the transport of mitochondrial components into extracellular vesicles (EVs) and induce tumor metastasis. Although HSP90 (heat shock protein 90) chaperones hundreds of client proteins and its inhibitors suppress tumors, HSP90 inhibitors-related chemotherapy is associated with unexpected metastasis. Herein, we find that HSP90 inhibitor causes mitochondrial damage but stimulates the low LC3-induced MDVs and the release of MDVs-derived EVs. However, why LC3 decreases and what is the transcriptional regulatory mechanism of MDVs formation under HSP90 inhibition remain unknown. Because TFEB (transcription factor EB) is the most important mitophagy transcription factor, and the HSP90 client HCFC1 (host cell factor C1) regulates <i>TFEB</i> transcription, there should be a hidden connection between TFEB, HCFC1 and HSP90 in MDVs formation. Our results support the idea that HSP90 N-terminal inhibition reduces <i>TFEB</i> transcription via decreased HSP90AA1-HCFC1 interaction, which prevents HCFC1 from binding to the <i>TFEB</i> proximal promoter region. Decreased <i>TFEB</i> transcription and consequently reduced LC3, ultimately promoted MDVs formation. Blocking MDVs formation with the microtubule inhibitor nocodazole (NOC) activates the HCFC1-<i>TFEB</i>-LC3 axis, weakens HSP90 inhibitors-induced MDVs and the release of MDVs-derived EVs, inhibits the growth of tumor cell spheres and primary liver tumors, and reduces the extravasation of cancer cells to secondary metastatic sites. Taken together, these data suggest that combination therapy should be used to reduce the metastatic risk of low <i>TFEB</i>-triggered-MDVs formation caused by HSP90 inhibitors.<b>Abbreviation</b>: ACIs: ATP-competitive inhibitors; BaFA1: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CTD: C-terminal domain; EVs: extracellular vesicles; HCFC1: host cell factor C1; HSP90: heat shock protein 90; ILVs: intralumenal vesicles; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MD: middle domain; MDVs: mitochondria-derived vesicles; MQC: mitochondrial quality control; ΔΨm: mitochondrial membrane potential; MVBs: multivesicular bodies; NB: novobiocin; TEM: transmission electron microscopy; TFEB: transcription factor EB; TFs: transcription factors. NOC: nocodazole; NTD: N-terminal nucleotide binding domain; OCR: oxygen consumption rate; RFP: red fluorescent protein; ROS: reactive oxygen species; STA9090: Ganetespib; VPS35: VPS35 retromer complex component.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514559","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":"Efficient PHB2 (prohibitin 2) exposure during mitophagy depends on VDAC1 (voltage dependent anion channel 1).","authors":"Moumita Roy, Sumangal Nandy, Elena Marchesan, Chayan Banerjee, Rupsha Mondal, Federico Caicci, Elena Ziviani, Joy Chakraborty","doi":"10.1080/15548627.2024.2426116","DOIUrl":"https://doi.org/10.1080/15548627.2024.2426116","url":null,"abstract":"<p><p>Exposure of inner mitochondrial membrane resident protein PHB2 (prohibitin 2) during autophagic removal of depolarized mitochondria (mitophagy) depends on the ubiquitin-proteasome system. This uncovering facilitates the PHB2 interaction with phagophore membrane-associated protein MAP1LC3/LC3. It is unclear whether PHB2 is exposed randomly at mitochondrial rupture sites. Prior knowledge and initial screening indicated that VDAC1 (voltage dependent anion channel 1) might play a role in this phenomenon. Through <i>in vitro</i> biochemical assays and imaging, we have found that VDAC1-PHB2 interaction increases during mitochondrial depolarization. Subsequently, this interaction enhances the efficiency of PHB2 exposure and mitophagy. To investigate the relevance <i>in vivo</i>, we utilized <i>porin</i> (equivalent to VDAC1) knockout <i>Drosophila</i> line. Our findings demonstrate that during mitochondrial stress, porin is essential for Phb2 exposure, Phb2-Atg8 interaction and mitophagy. This study highlights that VDAC1 predominantly synchronizes efficient PHB2 exposure through mitochondrial rupture sites during mitophagy. These findings may provide insights to understand progressive neurodegeneration.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607141","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":"PINK1-deficiency facilitates mitochondrial iron accumulation and colon tumorigenesis.","authors":"Mariella Arcos, Lavanya Goodla, Hyeoncheol Kim, Sharina P Desai, Rui Liu, Kunlun Yin, Zhaoli Liu, David R Martin, Xiang Xue","doi":"10.1080/15548627.2024.2425594","DOIUrl":"https://doi.org/10.1080/15548627.2024.2425594","url":null,"abstract":"<p><p>Mitophagy, the process by which cells eliminate damaged mitochondria, is mediated by PINK1 (PTEN induced kinase 1). Our recent research indicates that PINK1 functions as a tumor suppressor in colorectal cancer by regulating cellular metabolism. Interestingly, PINK1 ablation activated the NLRP3 (NLR family pyrin domain containing 3) inflammasome, releasing IL1B (interleukin 1 beta). However, inhibiting the NLRP3-IL1B signaling pathway with an IL1R (interleukin 1 receptor) antagonist or NLRP3 inhibitor did not hinder colon tumor growth after PINK1 loss. To identify druggable targets in PINK1-deficient tumors, ribonucleic acid sequencing analysis was performed on colon tumors from <i>pink1</i> knockout and wild-type mice. Gene Set Enrichment Analysis highlighted the enrichment of iron ion transmembrane transporter activity. Subsequent qualitative polymerase chain reaction and western blot analysis revealed an increase in mitochondrial iron transporters, including mitochondrial calcium uniporter, in PINK1-deficient colon tumor cells and tissues. Live-cell iron staining demonstrated elevated cellular and mitochondrial iron levels in PINK1-deficient cells. Clinically used drugs deferiprone and minocycline reduced mitochondrial iron and superoxide levels, resulting in decreased colon tumor cell growth <i>in vitro</i> and <i>in vivo</i>. Manipulating the mitochondrial iron uptake protein MCU (mitochondrial calcium uniporter) also affected cell and xenograft tumor growth. This study suggests that therapies aimed at reducing mitochondrial iron levels may effectively inhibit colon tumor growth, particularly in patients with low PINK1 expression.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607142","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":"https://doi.org/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.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-07","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":"Atractylenolide I inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through ATP6V0D2-mediated autophagic degradation of EPAS1/HIF2α.","authors":"Qinyu Li, Kai Zeng, Qian Chen, Chenglin Han, Xi Wang, Beining Li, Jianping Miao, Bolong Zheng, Jihong Liu, Xianglin Yuan, Bo Liu","doi":"10.1080/15548627.2024.2421699","DOIUrl":"10.1080/15548627.2024.2421699","url":null,"abstract":"<p><p>Clear cell renal cell carcinoma (ccRCC) is tightly associated with <i>VHL</i> (von Hippel-Lindau tumor suppressor) mutation and dysregulated angiogenesis. Accumulating evidence indicates that antiangiogenic treatment abolishing tumor angiogenesis can achieve longer disease-free survival in patients with ccRCC. Atractylenolide I (ATL-I) is one of the main active compounds in <i>Atractylodes macrocephala</i> root extract and exhibits various pharmacological effects, including anti-inflammatory and antitumor effects. In this study, we revealed the potent antitumor activity of ATL-I in ccRCC. ATL-I exhibited robust antiangiogenic capacity by inhibiting EPAS1/HIF2α-mediated VEGFA production in VHL-deficient ccRCC, and it promoted autophagic degradation of EPAS1 by upregulating the ATPase subunit ATP6V0D2 (ATPase H+ transporting V0 subunit d2) to increase lysosomal function and facilitated fusion between autophagosomes and lysosomes. Mechanistically, ATP6V0D2 directly bound to RAB7 and VPS41 and promoted the RAB7-HOPS interaction, facilitating SNARE complex assembly and autophagosome-lysosome fusion. Moreover, ATP6V0D2 promoted autolysosome degradation by increasing the acidification and activity of lysosomes during the later stages of macroautophagy/autophagy. Additionally, we found that ATL-I could decrease the level of EPAS1, which was upregulated in sunitinib-resistant cells, thus reversing sunitinib resistance. Collectively, our findings demonstrate that ATL-I is a robust antiangiogenic and antitumor lead compound with potential clinical application for ccRCC therapy.<b>Abbreviations</b>: ATL-I: atractylenolide I; ATP6V0D2: ATPase H+ transporting V0 subunit d2; CAM: chick chorioallantoic membrane; ccRCC: clear cell renal cell carcinoma; CTSB: cathepsin B; CTSD: cathepsin D; GO: Gene Ontology; HIF-1: HIF1A-ARNT heterodimer; HOPS: homotypic fusion and protein sorting; KDR/VEGFR: kinase insert domain receptor; KEGG: Kyoto Encyclopedia of Genes and Genomes; RCC: renal cell carcinoma; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TKI: tyrosine kinase inhibitor; V-ATPase: vacuolar-type H±translocating ATPase; VEGF: vascular endothelial growth factor; VHL: von Hippel-Lindau tumor suppressor.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549512","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":"Molecular mechanisms of ESCRT-mediated autophagosome maturation in plants.","authors":"Niccolò Mosesso, Erika Isono","doi":"10.1080/15548627.2024.2423327","DOIUrl":"10.1080/15548627.2024.2423327","url":null,"abstract":"<p><p>Diverse environmental stress factors affect the functionality of proteins and membrane compartments within cells causing potentially irremediable damage to the cell. A major process to eliminate nonfunctional molecular aggregates or damaged organelles under stress conditions is macroautophagy/autophagy, thus making its regulation critical for cellular adaptation and survival. The formation of autophagosomes is coordinated by a wide range of cellular factors and culminates in the closure of the cup-shaped double membrane or phagophore. The endosomal sorting complex required for transport (ESCRT) machinery has been proposed to mediate the sealing of the autophagic membranes. However, the molecular basis for ESCRT recruitment to phagophores under stress conditions are not yet fully understood. We recently described the role of ALIX (ALG-2 interacting protein-X) and its interactor CALB1 (Ca²⁺-dependent Lipid Binding protein 1) in autophagosome maturation during salt stress in Arabidopsis. Our study shows that CALB1 is important for phagophore closure and thus to the subsequent delivery to the vacuole. CALB1 localizes on salt-induced phagophores together with ALIX. CALB1 stimulates the phase separation of ALIX, which can facilitate the further ESCRT recruitment to phagophore membranes.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549514","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":"Dysregulation of pancreatic β-cell autophagy and the risk of type 2 diabetes.","authors":"Hayder M Al-Kuraishy, Majid S Jabir, Ali I Al-Gareeb, Daniel J Klionsky, Ali K Albuhadily","doi":"10.1080/15548627.2024.2367356","DOIUrl":"10.1080/15548627.2024.2367356","url":null,"abstract":"<p><p>Macroautophagy/autophagy is an essential degradation process that removes abnormal cellular components, maintains homeostasis within cells, and provides nutrition during starvation. Activated autophagy enhances cell survival during stressful conditions, although overactivation of autophagy triggers induction of autophagic cell death. Therefore, early-onset autophagy promotes cell survival whereas late-onset autophagy provokes programmed cell death, which can prevent disease progression. Moreover, autophagy regulates pancreatic β-cell functions by different mechanisms, although the precise role of autophagy in type 2 diabetes (T2D) is not completely understood. Consequently, this mini-review discusses the protective and harmful roles of autophagy in the pancreatic β cell and in the pathophysiology of T2D.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141319257","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":"Recycling the recyclers: lysophagy emerges as a new pharmacological target for retinal degeneration.","authors":"Juan Ignacio Jiménez-Loygorri, Patricia Boya","doi":"10.1080/15548627.2024.2391726","DOIUrl":"10.1080/15548627.2024.2391726","url":null,"abstract":"<p><p>Dysregulated macroautophagy/autophagy is one of the hallmarks of aging and has also been linked to higher incidence of several age-associated diseases such as age-related macular degeneration (AMD). The main cell type affected in AMD is the retinal pigment epithelium (RPE), and this disease can lead to central vision loss. Despite affecting around 8.7% of the population between 45-85 years, its etiopathogenesis remains unknown. In our recent manuscript using the pharmacological sodium iodate (SI) model of AMD we identified severe lysosomal membrane permeabilization (LMP) in the RPE, that leads to autophagy flux blockage and proteostasis defects. Treatment with the natural compound urolithin A (UA) reduces RPE cell death and alleviates vision loss, concurrent with full autophagy restoration. While UA was initially described as a specific mitophagy inducer, we now show that it is also able to promote SQSTM1/p62-dependent lysophagy in the context of lysosomal damage and LMP. Genetic downregulation of SQSTM1/p62 fully abolishes the effect of UA on lysophagy while mitophagy stimulation remains unaffected. In summary, these findings highlight the wide range of pathways modulated by UA and its potential implementation in the management of AMD and other diseases involving lysosomal damage.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918324","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":"Lassa virus Z protein hijacks the autophagy machinery for efficient transportation by interrupting CCT2-mediated cytoskeleton network formation.","authors":"Yueming Yuan, An Fang, Mai Zhang, Ming Zhou, Zhen F Fu, Ling Zhao","doi":"10.1080/15548627.2024.2379099","DOIUrl":"10.1080/15548627.2024.2379099","url":null,"abstract":"<p><p>The Lassa virus (LASV) is a widely recognized virulent pathogen that frequently results in lethal viral hemorrhagic fever (VHF). Earlier research has indicated that macroautophagy/autophagy plays a role in LASV replication, but, the precise mechanism is unknown. In this present study, we show that LASV matrix protein (LASV-Z) is essential for blocking intracellular autophagic flux. LASV-Z hinders actin and tubulin folding by interacting with CCT2, a component of the chaperonin-containing T-complexes (TRiC). When the cytoskeleton is disrupted, lysosomal enzyme transit is hampered. In addition, cytoskeleton disruption inhibits the merge of autophagosomes with lysosomes, resulting in autophagosome accumulation that promotes the budding of LASV virus-like particles (VLPs). Inhibition of LASV-Z-induced autophagosome accumulation blocks the LASV VLP budding process. Furthermore, it is found that glutamine at position 29 and tyrosine at position 48 on LASV-Z are important in interacting with CCT2. When these two sites are mutated, LASV-mut interacts with CCT2 less efficiently and can no longer inhibit the autophagic flux. These findings demonstrate a novel strategy for LASV-Z to hijack the host autophagy machinery to accomplish effective transportation.<b>Abbreviation:</b> 3-MA: 3-methyladenine; ATG5: autophagy related 5; ATG7: autophagy related 7; Baf-A1: bafilomycin A₁; CCT2: chaperonin containing TCP1 subunit 2; co-IP: co-immunoprecipitation; CTSD: cathepsin D; DAPI: 4',6-diamidino-2'-phenylindole; DMSO: dimethyl sulfoxide; EGFR: epidermal growth factor receptor; GFP: green fluorescent protein; hpi: hours post-infection; hpt: hours post-transfection; LAMP1: lysosomal-associated membrane protein 1; LASV: lassa virus; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; mCherry: red fluorescent protein; PM: plasma membrane; SQSTM1/p62: sequestosome 1; STX6: syntaxin 6; VLP: virus-like particle; TEM: transmission electron microscopy; TRiC: chaperonin-containing T-complex; WB: western blotting; μm: micrometer; μM: micromole.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141617785","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}