PDF(Pubmed)
Abstract：
Guard proteins initiate defense mechanisms upon sensing pathogen-encoded virulence factors. Successful viral pathogens likely inhibit guard protein activity, but these interactions have been largely undefined. Here, we demonstrate that the human pathogen herpes simplex virus 1 (HSV-1) stimulates and inhibits an antiviral pathway initiated by NLRP1, a guard protein that induces inflammasome formation and pyroptotic cell death when activated. Notably, HSV-1 infection of human keratinocytes promotes posttranslational modifications to NLRP1, consistent with MAPK-dependent NLRP1 activation, but does not result in downstream inflammasome formation. We identify infected cell protein 0 (ICP0) as the critical HSV-1 protein that is necessary and sufficient for inhibition of the NLRP1 pathway. Mechanistically, ICP0\'s cytoplasmic localization and function as an E3 ubiquitin ligase prevents proteasomal degradation of the auto-inhibitory NT-NLRP1 fragment, thereby preventing inflammasome formation. Further, we demonstrate that inhibiting this inflammasome is important for promoting HSV-1 replication. Thus, we have established a mechanism by which HSV-1 overcomes a guard-mediated antiviral defense strategy in humans.
摘要：
保护蛋白在感知病原体编码的毒力因子时启动防御机制。成功的病毒病原体可能抑制保护蛋白活性，但是这些相互作用在很大程度上是不确定的。这里,我们证明，人类病原体单纯疱疹病毒1（HSV-1）刺激和抑制由NLRP1启动的抗病毒途径，NLRP1是一种保护蛋白，在激活时诱导炎症体形成和焦化性细胞死亡。值得注意的是,人角质形成细胞的HSV-1感染促进对NLRP1的翻译后修饰，与MAPK依赖性NLRP1激活一致，但不会导致下游炎症小体的形成。我们将感染的细胞蛋白0（ICP0）鉴定为关键的HSV-1蛋白，该蛋白是抑制NLRP1途径所必需和足够的。机械上,ICP0的细胞质定位和作为E3泛素连接酶的功能可防止自抑制性NT-NLRP1片段的蛋白酶体降解，从而防止炎症小体的形成。Further,我们证明了抑制该炎症小体对于促进HSV-1复制是重要的。因此，我们已经建立了HSV-1克服人类守卫介导的抗病毒防御策略的机制。
