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.
Highlights
The membrane-associated RING-CH (MARCH) proteins are E3 ligases that regulate the stability of various cellular membrane proteins
Given that MARCH8 has been shown to downregulate the expression of several viral envelope proteins, we asked whether MARCH8 affects HA incorporation into influenza A virus (IAV) particles
MARCH8 strongly inhibited the infectivity of the reporter viruses that were pseudotyped with VSV glycoprotein, which is consistent with previous report[17] (Fig. 1a)
Summary
The membrane-associated RING-CH (MARCH) proteins are E3 ligases that regulate the stability of various cellular membrane proteins. 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. Some viruses including hepatitis C virus (HCV), Dengue virus, and Zika viruses recruit MARCH8 to ubiquitinate viral proteins and promote viral replication[21]. It appears that MARCH proteins have complex interactions with different viruses. Instead of targeting IAV envelope glycoprotein HA, MARCH8 catalyzes ubiquitination of M2 protein at position K78, leading to M2 degradation in lysosomes. A recombinant A/Puerto Rico/8/34 (PR8) H1N1 IAV carrying the K78R M2 protein becomes resistant to MARCH8 and exhibits greater virulence in mice
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