Opposing activities of IFITM proteins in SARS-CoV-2 infection.
Opposing activities of IFITM proteins in SARS-CoV-2 infection.
复制标题
SARS-COV-2感染中IFITM蛋白的相反活性。
DOI：
10.15252/embj.2020106501
复制
发表时间：
2021-02-01
期刊：
影响因子：
--
通讯作者：
Yount JS
中科院分区：
文献类型：
--
作者：
Shi G;Kenney AD;Kudryashova E;Zani A;Zhang L;Lai KK;Hall-Stoodley L;Robinson RT;Kudryashov DS;Compton AA;Yount JS
干扰素诱导的跨膜蛋白(IFITM)可抑制许多病毒的感染，但IFITM的一部分通过目前未知的机制增强特定冠状病毒的感染。我们发现SARS-CoV-2刺状伪型病毒和真正的SARS-CoV-2感染通常受人和鼠IFITM1、IFITM2和IFITM3的限制，使用功能获得和丧失的方法。从机制上讲，SARS-CoV-2的限制作用独立于IFITM3的S-棕榈酰化，这表明了一种不同于已报道的对其他病毒的抑制作用的限制能力。相反，IFITM3两亲性螺旋及其两亲性是限制病毒所必需的。IFITM3内吞YxxФ基序中残基的突变将人IFITM3转化为SARS-CoV-2感染的增强子，细胞对细胞融合试验证实了内吞突变体增强了Spike介导的与质膜的融合。TMPRSS2的过表达增加了SARS-CoV-2的质膜融合和内体融合，减弱了IFITM3的限制，并将两亲性螺旋突变体转化为感染增强剂。总而言之，我们发现了IFITM3的新的亲病毒和抗病毒机制，在增强质膜上的病毒感染和用于内体限制SARS-CoV-2的两亲性机制之间有明显的区别。虽然IFITM家族宿主细胞抗病毒因子通常限制SARS-CoV-2感染，但令人惊讶的是，人类IFITM3既具有抗病毒作用，又具有亲病毒作用，既抑制了病毒的内吞，又促进了病毒在质膜上的融合。
Interferon‐induced transmembrane proteins (IFITMs) restrict infections by many viruses, but a subset of IFITMs enhance infections by specific coronaviruses through currently unknown mechanisms. We show that SARS‐CoV‐2 Spike‐pseudotyped virus and genuine SARS‐CoV‐2 infections are generally restricted by human and mouse IFITM1, IFITM2, and IFITM3, using gain‐ and loss‐of‐function approaches. Mechanistically, SARS‐CoV‐2 restriction occurred independently of IFITM3 S‐palmitoylation, indicating a restrictive capacity distinct from reported inhibition of other viruses. In contrast, the IFITM3 amphipathic helix and its amphipathic properties were required for virus restriction. Mutation of residues within the IFITM3 endocytosis‐promoting YxxФ motif converted human IFITM3 into an enhancer of SARS‐CoV‐2 infection, and cell‐to‐cell fusion assays confirmed the ability of endocytic mutants to enhance Spike‐mediated fusion with the plasma membrane. Overexpression of TMPRSS2, which increases plasma membrane fusion versus endosome fusion of SARS‐CoV‐2, attenuated IFITM3 restriction and converted amphipathic helix mutants into infection enhancers. In sum, we uncover new pro‐ and anti‐viral mechanisms of IFITM3, with clear distinctions drawn between enhancement of viral infection at the plasma membrane and amphipathicity‐based mechanisms used for endosomal SARS‐CoV‐2 restriction. While IFITM‐family host‐cell antiviral factors generally restrict SARS‐CoV‐2 infection, human IFITM3 surprisingly exhibits both anti‐ and pro‐viral effects, inhibiting endocytic entry of the virus while also enhancing virus fusion at the plasma membrane.