A viral ubiquitin ligase has substrate preferential SUMO targeted ubiquitin ligase activity that counteracts intrinsic antiviral defence.
A viral ubiquitin ligase has substrate preferential SUMO targeted ubiquitin ligase activity that counteracts intrinsic antiviral defence.
复制标题
病毒的泛素连接酶具有抵抗内在抗病毒药防御的底物优先SUMO靶向泛素连接酶活性。
DOI：
10.1371/journal.ppat.1002245
复制
发表时间：
2011-09
期刊：
影响因子：
6.7
通讯作者：
Everett RD
中科院分区：
文献类型：
--
作者：
Boutell C;Cuchet-Lourenço D;Vanni E;Orr A;Glass M;McFarlane S;Everett RD
内在的抗病毒抗性代表了细胞内抵抗病毒感染的第一道防线。在单纯疱疹病毒1型（HSV-1）感染期间，这种反应可导致病毒基因表达的抑制，但被病毒泛素连接酶ICP 0抵消。在这里，我们解决的机制，ICP 0克服这种抗病毒反应。我们报告说，ICP 0诱导广泛的蛋白酶体依赖性降解的SUMO结合蛋白在感染过程中，并具有相关的细胞SUMO靶向泛素连接酶（STUBLs）的属性。ICP 0内假定的SUMO相互作用基序的突变不仅影响其降解SUMO缀合物的能力，而且影响其刺激HSV-1裂解感染和从静止再活化的能力。我们证明，在没有这种病毒对策的SUMO结合途径介导的内在抗病毒耐药性和抑制HSV-1感染中起着重要的作用。使用PML作为模型底物，我们发现，虽然ICP 0优先靶向SUMO修饰的PML亚型进行降解，但它也以SUMO修饰独立的方式诱导PML亚型I的降解。PML被ICP 0降解的速度通常比SUMO修饰的蛋白质更快，这意味着SUMO修饰蛋白质的身份以及SUMO修饰的存在与ICP 0靶向有关。我们的结论是，ICP 0具有双重靶向机制，涉及SUMO和底物依赖性靶向特异性，以抵消对HSV-1感染的内在抗病毒耐药性。病毒必须逃避几种抗病毒防御，以建立生产性感染。这些包括抗体和细胞介导的获得性免疫和干扰素调节的先天免疫。最近，人们发现了抗病毒防御的第三种武器，即所谓的内在免疫。抗病毒抗性的这一方面代表了针对病毒感染的细胞内防御的第一道防线，并且由预先存在的细胞因子介导，这些细胞因子试图在感染的初始阶段抑制病毒复制。像获得性免疫和先天免疫一样，病毒也进化出了克服内在防御的机制。在这里，我们表明，在应对单纯疱疹病毒1型（HSV-1）感染的一个重要方面的内在免疫调节的小泛素样修饰（SUMO）共轭途径。作为对这种防御的响应，病毒诱导特异性SUMO缀合蛋白的快速降解，随后通常引起SUMO缀合种类的广泛损失。SUMO途径的失活抑制了细胞在没有这种病毒对策的情况下有效抑制病毒复制的能力。我们的数据确定了介导对HSV-1感染的内在抗性的重要调控途径，并描述了病毒利用以抵消这种抗病毒防御的生化机制。
Intrinsic antiviral resistance represents the first line of intracellular defence against virus infection. During herpes simplex virus type-1 (HSV-1) infection this response can lead to the repression of viral gene expression but is counteracted by the viral ubiquitin ligase ICP0. Here we address the mechanisms by which ICP0 overcomes this antiviral response. We report that ICP0 induces the widespread proteasome-dependent degradation of SUMO-conjugated proteins during infection and has properties related to those of cellular SUMO-targeted ubiquitin ligases (STUbLs). Mutation of putative SUMO interaction motifs within ICP0 not only affects its ability to degrade SUMO conjugates, but also its capacity to stimulate HSV-1 lytic infection and reactivation from quiescence. We demonstrate that in the absence of this viral countermeasure the SUMO conjugation pathway plays an important role in mediating intrinsic antiviral resistance and the repression of HSV-1 infection. Using PML as a model substrate, we found that whilst ICP0 preferentially targets SUMO-modified isoforms of PML for degradation, it also induces the degradation of PML isoform I in a SUMO modification-independent manner. PML was degraded by ICP0 more rapidly than the bulk of SUMO-modified proteins in general, implying that the identity of a SUMO-modified protein, as well as the presence of SUMO modification, is involved in ICP0 targeting. We conclude that ICP0 has dual targeting mechanisms involving both SUMO- and substrate-dependent targeting specificities in order to counteract intrinsic antiviral resistance to HSV-1 infection. Viruses must evade several antiviral defences in order to establish a productive infection. These include antibody- and cell-mediated acquired immunity and interferon-regulated innate immunity. Recently, a third arm of antiviral defence has been discovered, so called intrinsic immunity. This aspect of antiviral resistance represents the first line of intracellular defence against virus infection and is mediated by pre-existing cellular factors that attempt to repress viral replication during the initial stages of infection. Like acquired and innate immunity, viruses have evolved mechanisms that overcome intrinsic defence. Here we show that in response to herpes simplex virus type-1 (HSV-1) infection an important aspect of intrinsic immunity is regulated by the small ubiquitin-like modifier (SUMO) conjugation pathway. In response to this defence, the virus induces rapid degradation of specific SUMO-conjugated proteins, followed by widespread loss of SUMO-conjugated species in general. Inactivation of the SUMO pathway inhibits the cell’s ability to efficiently repress viral replication in the absence of this viral countermeasure. Our data identifies an important regulatory pathway that mediates intrinsic resistance to HSV-1 infection and describes the biochemical mechanism that the virus utilizes in order to counteract this antiviral defence.
登录
查看更多内容
影响因子：
5.4
作者：
Davido, DJ;von Zagorski, WF;Schaffer, PA
通讯作者：
Schaffer, PA
影响因子：
16
作者：
Boggio, R;Colombo, R;Chiocca, S
通讯作者：
Chiocca, S
影响因子：
5.4
作者：
Boutell, Chris;Everett, Roger;Davido, David
通讯作者：
Davido, David
影响因子：
5.4
作者：
Everett, RD;Boutell, C;Orr, A
通讯作者：
Orr, A
影响因子：
5.4
作者：
Berndt, Anja;Hofmann-Winkler, Heike;Stamminger, Thomas
通讯作者：
Stamminger, Thomas