MARCH8 inhibits influenza A virus infection by targeting viral M2 protein for ubiquitination-dependent degradation in lysosomes

Xiaoman Liu, Fengwen Xu, Lili Ren, Fei Zhao, Yu Huang, Liang Wei, Yingying Wang, Conghui Wang, Zhangling Fan, Shan Mei, Jingdong Song, Zhendong Zhao, Shan Cen, Chen Liang, Jianwei Wang () and Fei Guo ()
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Xiaoman Liu: Chinese Academy of Medical Sciences & Peking Union Medical College
Fengwen Xu: Chinese Academy of Medical Sciences & Peking Union Medical College
Lili Ren: Chinese Academy of Medical Sciences & Peking Union Medical College
Fei Zhao: Chinese Academy of Medical Sciences & Peking Union Medical College
Yu Huang: Chinese Academy of Medical Sciences & Peking Union Medical College
Liang Wei: Chinese Academy of Medical Sciences & Peking Union Medical College
Yingying Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Conghui Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Zhangling Fan: Chinese Academy of Medical Sciences & Peking Union Medical College
Shan Mei: Chinese Academy of Medical Sciences & Peking Union Medical College
Jingdong Song: Chinese Center for Disease Control and Prevention
Zhendong Zhao: Chinese Academy of Medical Sciences & Peking Union Medical College
Shan Cen: Chinese Academy of Medical Sciences & Peking Union Medical College
Chen Liang: McGill University AIDS Centre, Lady Davis Institute, Jewish General Hospital
Jianwei Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Fei Guo: Chinese Academy of Medical Sciences & Peking Union Medical College

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract The membrane-associated RING-CH (MARCH) proteins are E3 ligases that regulate the stability of various cellular membrane proteins. MARCH8 has been reported to inhibit the infection of HIV-1 and a few other viruses, thus plays an important role in host antiviral defense. However, the antiviral spectrum and the underlying mechanisms of MARCH8 are incompletely defined. Here, we demonstrate that MARCH8 profoundly inhibits influenza A virus (IAV) replication both in vitro and in mice. Mechanistically, MARCH8 suppresses IAV release through redirecting viral M2 protein from the plasma membrane to lysosomes for degradation. Specifically, MARCH8 catalyzes the K63-linked polyubiquitination of M2 at lysine residue 78 (K78). A recombinant A/Puerto Rico/8/34 virus carrying the K78R M2 protein shows greater replication and more severe pathogenicity in cells and mice. More importantly, we found that the M2 protein of the H1N1 IAV has evolved to acquire non-lysine amino acids at positions 78/79 to resist MARCH8-mediated ubiquitination and degradation. Together, our data support the important role of MARCH8 in host anti-IAV intrinsic immune defense by targeting M2, and suggest the inhibitory pressure of MARCH8 on H1N1 IAV transmission in the human population.

Date: 2021
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DOI: 10.1038/s41467-021-24724-2

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