NHC Key Laboratory of Systems Biology of Pathogens and Center for AIDS Research, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
NHC Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Nat Commun. 2021 Jul 20;12(1):4427. doi: 10.1038/s41467-021-24724-2.
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.
膜相关环指 E3 连接酶（MARCH）蛋白是一类 E3 连接酶，可调节各种细胞膜蛋白的稳定性。已有报道称 MARCH8 可抑制 HIV-1 及其他几种病毒的感染，因此在宿主抗病毒防御中发挥重要作用。然而，MARCH8 的抗病毒谱和潜在机制尚未完全确定。在这里，我们证明 MARCH8 可显著抑制甲型流感病毒（IAV）在体外和体内的复制。在机制上，MARCH8 通过将病毒 M2 蛋白从质膜重新定向到溶酶体进行降解来抑制 IAV 的释放。具体而言，MARCH8 可催化 M2 在赖氨酸残基 78（K78）上的 K63 连接多泛素化。携带 K78R M2 蛋白的重组 A/Puerto Rico/8/34 病毒在细胞和小鼠中显示出更强的复制能力和更严重的致病性。更重要的是，我们发现 H1N1 IAV 的 M2 蛋白已进化为在位置 78/79 获得非赖氨酸氨基酸，以抵抗 MARCH8 介导的泛素化和降解。总之，我们的数据支持 MARCH8 通过靶向 M2 发挥重要作用，从而在宿主抗 IAV 固有免疫防御中发挥作用，并提示 MARCH8 对人群中 H1N1 IAV 传播的抑制作用。
