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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.<\/jats:p>","DOI":"10.1038\/s41467-021-24724-2","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T10:26:57Z","timestamp":1626776817000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":89,"title":["MARCH8 inhibits influenza A virus infection by targeting viral M2 protein for ubiquitination-dependent degradation in lysosomes"],"prefix":"10.1038","volume":"12","author":[{"given":"Xiaoman","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengwen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conghui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangling","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingdong","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhendong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Cen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1116-4559","authenticated-orcid":false,"given":"Jianwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3500-1006","authenticated-orcid":false,"given":"Fei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,20]]},"reference":[{"key":"24724_CR1","doi-asserted-by":"publisher","first-page":"341","DOI":"10.4049\/jimmunol.177.1.341","volume":"177","author":"M Ohmura-Hoshino","year":"2006","unstructured":"Ohmura-Hoshino, M. et al. Inhibition of MHC class II expression and immune responses by c-MIR. J. Immunol. 177, 341\u2013354 (2006).","journal-title":"J. Immunol."},{"key":"24724_CR2","doi-asserted-by":"crossref","unstructured":"Bartee, E. et al. Membrane-associated RING-CH proteins associate with Bap31 and target CD81 and CD44 to lysosomes. PLoS ONE 5, e15132 (2010).","DOI":"10.1371\/journal.pone.0015132"},{"key":"24724_CR3","doi-asserted-by":"publisher","first-page":"14128","DOI":"10.1073\/pnas.1205246109","volume":"109","author":"R Chen","year":"2012","unstructured":"Chen, R., Li, M., Zhang, Y., Zhou, Q. & Shu, H. B. The E3 ubiquitin ligase MARCH8 negatively regulates IL-1beta-induced NF-kappaB activation by targeting the IL1RAP coreceptor for ubiquitination and degradation. Proc. Natl Acad. Sci. USA 109, 14128\u201314133 (2012).","journal-title":"Proc. Natl Acad. Sci. 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