MARCH8 inhibits influenza A virus infection by targeting viral M2 protein for ubiquitination-dependent degradation in lysosomes.
MARCH8 inhibits influenza A virus infection by targeting viral M2 protein for ubiquitination-dependent degradation in lysosomes.
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MARCH8通过靶向病毒M2蛋白在溶酶体中泛素化依赖的降解来抑制甲型流感病毒的感染。
DOI：
10.1038/s41467-021-24724-2
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发表时间：
2021-07-20
影响因子：
16.6
通讯作者：
Guo F
中科院分区：
文献类型：
--
作者：
Liu X;Xu F;Ren L;Zhao F;Huang Y;Wei L;Wang Y;Wang C;Fan Z;Mei S;Song J;Zhao Z;Cen S;Liang C;Wang J;Guo F
膜相关RING-CH（MARCH）蛋白是调节各种细胞膜蛋白稳定性的E3连接酶。据报道，MARCH 8可以抑制HIV-1和其他一些病毒的感染，因此在宿主的抗病毒防御中起着重要作用。然而，MARCH 8的抗病毒谱和潜在机制尚未完全确定。在这里，我们证明了MARCH 8在体外和小鼠中都能深刻地抑制甲型流感病毒（IAV）的复制。在机制上，MARCH 8通过将病毒M2蛋白从质膜重定向到溶酶体进行降解来抑制IAV释放。具体来说，MARCH 8催化M2在赖氨酸残基78（K78）处的K63连接的聚遍在蛋白化。携带K78 R M2蛋白的重组A/波多黎各/8/34病毒在细胞和小鼠中显示出更大的复制和更严重的致病性。更重要的是，我们发现H1N1 IAV的M2蛋白已经进化到在78/79位获得非赖氨酸氨基酸，以抵抗MARCH 8介导的泛素化和降解。总之，我们的数据支持MARCH 8通过靶向M2在宿主抗IAV内在免疫防御中的重要作用，并表明MARCH 8对H1N1 IAV在人群中传播的抑制压力。膜相关RING-CH（MARCH）蛋白是调节质膜（PM）蛋白稳定性的E3连接酶。在此，Liu等人表明，MARCH 8通过将M2蛋白从PM重定向至溶酶体进行降解，在体外和体内抑制甲型流感病毒感染。
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. The membrane-associated RING-CH (MARCH) proteins are E3 ligases regulating stability of plasma membrane (PM) proteins. Here, Liu et al. show that MARCH8 suppresses Influenza A virus infection in vitro and in vivo through redirecting M2 protein from the PM to lysosomes for degradation.
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影响因子：
16.6
作者：
Nagarajan, Arvindhan;Petersen, Max C.;Nasiri, Ali R.;Butrico, Gina;Fung, Annie;Ruan, Hai-Bin;Kursawe, Romy;Caprio, Sonia;Thibodeau, Jacques;Bourgeois-Daigneault, Marie-Claude;Sun, Lisha;Gao, Guangping;Bhanot, Sanjay;Jurczak, Michael J.;Green, Michael R.;Shulman, Gerald I.;Wajapeyee, Narendra
通讯作者：
Wajapeyee, Narendra
影响因子：
6.7
作者：
Mänz B;Dornfeld D;Götz V;Zell R;Zimmermann P;Haller O;Kochs G;Schwemmle M
通讯作者：
Schwemmle M
DOI：
10.1073/pnas.1507981112
发表时间：
2015-08-18
影响因子：
11.1
作者：
Cho, Kyung-Jin;Walseng, Even;Roche, Paul A.
通讯作者：
Roche, Paul A.
BST-2 限制 IAV 释放并被病毒 M2 蛋白对抗。
影响因子：
4.1
作者：
Hu, Siqi;Yin, Lijuan;Guo, Fei
通讯作者：
Guo, Fei
DOI：
10.1084/jem.20160312
发表时间：
2016-08-22
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Liu H;Jain R;Guan J;Vuong V;Ishido S;La Gruta NL;Gray DH;Villadangos JA;Mintern JD
通讯作者：
Mintern JD