The role of TRIM-family proteins and other host cell factors in the restriction of SARS-CoV-2

我们假设迄今尚未确定的TRIM蛋白在限制冠状病毒宿主易感性和裂解复制中起关键作用。冠状病毒感染的特点是病毒大量复制。对调节裂解复制易感性的因素的分子洞察是至关重要的，特别是在明显的性别相关差异方面。尽管在确定调节病毒附着和融合的病毒因子方面取得了重大进展，但我们对调节复制的宿主内在因子的了解仍处于初级阶段。Tripartite motif （TRIM）蛋白被越来越多地认为是重要的抗病毒（也是前病毒）因子，可以调节多种RNA病毒和DNA病毒的复制。TRIM蛋白可以通过直接靶向病毒成分或调节导致抗病毒基因表达的先天免疫反应来抑制病毒复制。抗病毒限制的机制通常依赖于TRIM E3连接酶的功能，其靶向病毒或宿主蛋白进行蛋白酶体降解。另一个例子是，TRIM19（也称为早幼粒细胞白血病蛋白，PML）通过组织PML核体，特别是在对干扰素的反应中，限制多种RNA病毒和DNA病毒[见5,6]。我们将1)鉴定限制SARS-CoV-2的TRIM家族蛋白，2)开始描述已鉴定的限制SARS-CoV-2的TRIMs的机制。使用我们实验室开发的复制子标记系统和CRISPR敲除将为后续的研究项目指明方向。如果我们的研究确定了TRIM蛋白在对抗冠状病毒感染的内在免疫和宿主细胞相互作用中的作用，这可能是治疗干预的目标。

We postulate that hitherto unidentified TRIM proteins play critical roles in restricting Betacoronavirus host susceptibility and lytic replication. Coronavirus infection is characterized by productive viral replication. Molecular insight into the factors that modulate the susceptibility to lytic replication is of fundamental importance, in particular also with respect to obvious gender-related differences. Although major progress has been made towards identifying the viral factors that regulate virus attachment and fusion, our knowledge of host intrinsic factors that modulate replication is still rudimentary. Tripartite motif (TRIM) proteins are increasingly recognized as important antiviral (and also proviral) factors that modulate the replication of a wide range of RNA viruses and DNA viruses. TRIM proteins can inhibit viral replication by either directly targeting viral components or modulating the innate immune responses that result in antiviral gene expression. The mechanism of antiviral restriction often relies in the TRIM E3 ligase functions, which target viral or host proteins for proteasomal degradation. As another example, TRIM19 (also known as promyelocytic leukaemia protein, PML) restricts multiple RNA viruses and DNA viruses, by organizing PML nuclear bodies, in particular also in response to interferons [reviewed in 5, 6]. We will 1) identify TRIM family proteins restricting SARS-CoV-2, and 2) start to delineate the mechanism of identified SARS-CoV-2-restricting TRIMs. Using a replicon-marker system, which was developed in our lab and 3) CRISPR knockout will point out directions for continued research projects. If our study identifies a role of a TRIM protein in intrinsic immunity and host cell interaction against Coronavirus infection, this may be targeted for therapeutic intervention.