自噬
生物
细胞生物学
袋3
自噬体
ULK1
死孢子体1
溶酶体
PI3K/AKT/mTOR通路
自噬相关蛋白13
冠状病毒
病毒学
激酶
蛋白激酶A
信号转导
安普克
生物化学
细胞凋亡
酶
病理
传染病(医学专业)
蛋白质磷酸化
疾病
医学
2019年冠状病毒病(COVID-19)
作者
Peili Hou,Xuefeng Wang,Hongmei Wang,Tiecheng Wang,Zhangping Yu,Chunqing Xu,Yingxin Zhao,Wenqi Wang,Yong Zhao,Fengyun Chu,Huasong Chang,Hongchao Zhu,Jiahui Lu,Fuzhen Zhang,Xue Li,Xingyu Li,Song Wang,Yuwei Gao,Hongbin He
出处
期刊:Autophagy
[Informa]
日期:2022-06-19
卷期号:19 (2): 551-569
被引量:50
标识
DOI:10.1080/15548627.2022.2084686
摘要
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is closely related to various cellular aspects associated with autophagy. However, how SARS-CoV-2 mediates the subversion of the macroautophagy/autophagy pathway remains largely unclear. In this study, we demonstrate that overexpression of the SARS-CoV-2 ORF7a protein activates LC3-II and leads to the accumulation of autophagosomes in multiple cell lines, while knockdown of the viral ORF7a gene via shRNAs targeting ORF7a sgRNA during SARS-CoV-2 infection decreased autophagy levels. Mechanistically, the ORF7a protein initiates autophagy via the AKT-MTOR-ULK1-mediated pathway, but ORF7a limits the progression of autophagic flux by activating CASP3 (caspase 3) to cleave the SNAP29 protein at aspartic acid residue 30 (D30), ultimately impairing complete autophagy. Importantly, SARS-CoV-2 infection-induced accumulated autophagosomes promote progeny virus production, whereby ORF7a downregulates SNAP29, ultimately resulting in failure of autophagosome fusion with lysosomes to promote viral replication. Taken together, our study reveals a mechanism by which SARS-CoV-2 utilizes the autophagic machinery to facilitate its own propagation via ORF7a.Abbreviations: 3-MA: 3-methyladenine; ACE2: angiotensin converting enzyme 2; ACTB/β-actin: actin beta; ATG7: autophagy related 7; Baf A1: bafilomycin A1; BECN1: beclin 1; CASP3: caspase 3; COVID-19: coronavirus disease 2019; GFP: green fluorescent protein; hpi: hour post-infection; hpt: hour post-transfection; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MERS: Middle East respiratory syndrome; MTOR: mechanistic target of rapamycin kinase; ORF: open reading frame; PARP: poly(ADP-ribose) polymerase; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; shRNAs: short hairpin RNAs; siRNA: small interfering RNA; SNAP29: synaptosome associated protein 29; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TCID50: tissue culture infectious dose; TEM: transmission electron microscopy; TUBB, tubulin, beta; ULK1: unc-51 like autophagy activating kinase 1.
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