SARS-CoV-2 hijacks p38β/MAPK11 to promote virus replication.
SARS-CoV-2 hijacks p38β/MAPK11 to promote virus replication.
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严重急性呼吸综合征冠状病毒2号(SARS-CoV-2)是冠状病毒病2019年(新冠肺炎)大流行的病原体，它大幅修改受感染的细胞以优化病毒复制。其中一个这样的修饰是宿主p38丝裂原活化蛋白激酶(MAPK)通路的激活，该通路在炎性细胞因子的产生中发挥主要作用，炎性细胞因子的产生是严重新冠肺炎的一个特征。我们先前证明，抑制SARS-CoV-2感染细胞中p38/MAPK的活性会减少细胞因子的产生和病毒的复制。在这里，我们结合定量基因筛查、基因组学、蛋白质组学和磷酸蛋白质组学来更好地了解SARS-CoV-2依赖p38途径的潜在机制。我们发现，p38β是SARS-CoV-2在多个相关细胞系中复制的关键宿主因子，并且在病毒表达之后发挥作用。我们在SARS-CoV-2感染的背景下鉴定了假定的宿主和病毒p38β底物，并发现大多数宿主底物具有内在的抗病毒活性。综上所述，这项研究揭示了p38β的独特前病毒功能，并支持探索p38β抑制剂的开发作为创建新的新冠肺炎疗法类别的策略。SARS-CoV-2是新冠肺炎大流行的病原体，自2019年出现以来，已导致数以百万计的人死亡。SARS-CoV-2感染人类细胞需要几条细胞通路的激活才能成功复制。其中一个途径，p38MAPK途径，是病毒复制和疾病发病所必需的。在这里，我们应用系统生物学的方法来理解MAPK通路如何有利于SARS-CoV-2的复制，从而为新型新冠肺炎药物疗法的开发提供信息。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, drastically modifies infected cells to optimize virus replication. One such modification is the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammatory cytokine production, a hallmark of severe COVID-19. We previously demonstrated that inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduced both cytokine production and viral replication. Here, we combined quantitative genetic screening, genomics, proteomics, and phosphoproteomics to better understand mechanisms underlying the dependence of SARS-CoV-2 on the p38 pathway. We found that p38β is a critical host factor for SARS-CoV-2 replication in multiple relevant cell lines and that it functions at a step after viral mRNA expression. We identified putative host and viral p38β substrates in the context of SARS-CoV-2 infection and found that most host substrates have intrinsic antiviral activities. Taken together, this study reveals a unique proviral function for p38β and supports exploring p38β inhibitor development as a strategy toward creating a new class of COVID-19 therapies. SARS-CoV-2 is the causative agent of the COVID-19 pandemic that has claimed millions of lives since its emergence in 2019. SARS-CoV-2 infection of human cells requires the activity of several cellular pathways for successful replication. One such pathway, the p38 MAPK pathway, is required for virus replication and disease pathogenesis. Here, we applied systems biology approaches to understand how MAPK pathways benefit SARS-CoV-2 replication to inform the development of novel COVID-19 drug therapies.
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