Yabin Zhang1, Hao Sun2, Rongjuan Pei2, Binli Mao3, Zhenyu Zhao3, Huihui Li4, Yong Lin5, Kefeng Lu6. 1. Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and The Research Units of West China, Chinese Academy of Medical Sciences, Chengdu, China. 2. Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China. 3. Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China. 4. West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China. huihuili@scu.edu.cn. 5. Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Department of Infectious Diseases, The Second Affiliated Hospital, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China. linyong@cqmu.edu.cn. 6. Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and The Research Units of West China, Chinese Academy of Medical Sciences, Chengdu, China. lukf@scu.edu.cn.
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing coronavirus disease 2019 pandemic. How SARS-CoV-2 regulates cellular responses to escape clearance by host cells is unknown. Autophagy is an intracellular lysosomal degradation pathway for the clearance of various cargoes, including viruses. Here, we systematically screened 28 viral proteins of SARS-CoV-2 and identified that ORF3a strongly inhibited autophagic flux by blocking the fusion of autophagosomes with lysosomes. ORF3a colocalized with lysosomes and interacted with VPS39, a component of the homotypic fusion and protein sorting (HOPS) complex. The ORF3a-VPS39 interaction prohibited the binding of HOPS with RAB7, which prevented the assembly of fusion machinery, leading to the accumulation of unfused autophagosomes. These results indicated the potential mechanism by which SARS-CoV-2 escapes degradation; that is, the virus interferes with autophagosome-lysosome fusion. Furthermore, our findings will facilitate strategies targeting autophagy for conferring potential protection against the spread of SARS-CoV-2.
Severe acute respiratory syndrome coronavirus 2 (n class="Species">SARS-CoV-2) has caused the ongoing coronavirus disease 2019 pandemic. How SARS-CoV-2 regulates cellular responses to escape clearance by host cells is unknown. Autophagy is an intracellular lysosomal degradation pathway for the clearance of various cargoes, including viruses. Here, we systematically screened 28 viral proteins of SARS-CoV-2 and identified that ORF3a strongly inhibited autophagic flux by blocking the fusion of autophagosomes with lysosomes. ORF3a colocalized with lysosomes and interacted with VPS39, a component of the homotypic fusion and protein sorting (HOPS) complex. The ORF3a-VPS39 interaction prohibited the binding of HOPS with RAB7, which prevented the assembly of fusion machinery, leading to the accumulation of unfused autophagosomes. These results indicated the potential mechanism by which SARS-CoV-2 escapes degradation; that is, the virus interferes with autophagosome-lysosome fusion. Furthermore, our findings will facilitate strategies targeting autophagy for conferring potential protection against the spread of SARS-CoV-2.
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