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

AI Article Synopsis

  • - MARCH8 is an E3 ligase that helps regulate the stability of membrane proteins and is known to inhibit HIV-1 and other viruses, playing a key role in antiviral defense.
  • - Research shows that MARCH8 significantly reduces influenza A virus (IAV) replication by redirecting the viral M2 protein for degradation via lysosomes.
  • - The study reveals that the M2 protein of H1N1 IAV has evolved to resist MARCH8's action, indicating that MARCH8 plays a crucial role in host defenses against IAV and highlights its evolutionary impact on viral transmission in humans.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292393PMC
http://dx.doi.org/10.1038/s41467-021-24724-2DOI Listing

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