2. Academic Validation
  3. ATAD1 inhibits hepatitis C virus infection by removing the viral TA-protein NS5B from mitochondria

ATAD1 inhibits hepatitis C virus infection by removing the viral TA-protein NS5B from mitochondria

  • EMBO Rep. 2023 Oct 3:e56614. doi: 10.15252/embr.202256614.
Qing Zhou # 1 2 3,  Yuhao Yang # 1,  Zhanxue Xu 1,  Kai Deng 1 4,  Zhenzhen Zhang 1,  Jiawei Hao 1,  Ni Li 1 3,  Yanling Wang 1,  Ziwen Wang 5,  Haihang Chen 1,  Yang Yang 1,  Fei Xiao 6,  Xiaohong Zhang 3,  Song Gao 5,  Yi-Ping Li 1 3 6
Affiliations

Affiliations

  • 1 Institute of Human Virology, Department of Pathogen Biology and Biosecurity, and Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 2 Technology Center, China Tobacco Henan Industrial Co., Ltd, Zhengzhou, China.
  • 3 Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 4 Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
  • 5 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 6 Department of Infectious Disease, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.
  • # Contributed equally.
PMID: 37789674 DOI: 10.15252/embr.202256614
Abstract

ATPase family AAA domain-containing protein 1 (ATAD1) maintains mitochondrial homeostasis by removing mislocalized tail-anchored (TA) proteins from the mitochondrial outer membrane (MOM). Hepatitis C virus (HCV) Infection induces mitochondrial fragmentation, and viral NS5B protein is a TA protein. Here, we investigate whether ATAD1 plays a role in regulating HCV Infection. We find that HCV Infection has no effect on ATAD1 expression, but knockout of ATAD1 significantly enhances HCV infection; this enhancement is suppressed by ATAD1 complementation. NS5B partially localizes to mitochondria, dependent on its transmembrane domain (TMD), and induces mitochondrial fragmentation, which is further enhanced by ATAD1 knockout. ATAD1 interacts with NS5B, dependent on its three internal domains (TMD, pore-loop 1, and pore-loop 2), and induces the proteasomal degradation of NS5B. In addition, we provide evidence that ATAD1 augments the Antiviral function of MAVS upon HCV Infection. Taken together, we show that the mitochondrial quality control exerted by ATAD1 can be extended to a novel Antiviral function through the extraction of the viral TA-protein NS5B from the mitochondrial outer membrane.

Keywords

hepatitis C virus infection; mitochondria; protein degradation; protein interaction; tail-anchored protein.

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