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.

中文翻译：

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IFITM 蛋白在 SARS-CoV-2 感染中的相反活性


干扰素诱导跨膜蛋白（IFITM）可限制许多病毒的感染，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。我们使用功能获得和丧失的方法表明，SARS-CoV-2 Spike 假型病毒和真正的 SARS-CoV-2 感染通常受到人类和小鼠 IFITM1、IFITM2 和 IFITM3 的限制。从机制上讲，SARS-CoV-2 的限制独立于 IFITM3 S-棕榈酰化而发生，表明其限制能力不同于报道的其他病毒的抑制作用。相比之下，IFITM3 两亲螺旋及其两亲特性是病毒限制所必需的。 IFITM3 内吞促进 YxxФ 基序内残基的突变将人 IFITM3 转化为 SARS-CoV-2 感染的增强子，细胞间融合测定证实了内吞突变体增强 Spike 介导的与质膜融合的能力。 TMPRSS2 的过度表达可增加 SARS-CoV-2 的质膜融合与内体融合，减弱 IFITM3 限制并将两亲性螺旋突变体转化为感染增强子。总之，我们发现了 IFITM3 新的促病毒和抗病毒机制，在质膜处的病毒感染增强和用于限制内体 SARS-CoV-2 的基于两亲性的机制之间存在明显的区别。