SARS-CoV-2 Disrupts Proximal Elements in the JAK-STAT Pathway.
SARS-CoV-2 Disrupts Proximal Elements in the JAK-STAT Pathway.
复制标题
DOI：
10.1128/jvi.00862-21
复制
发表时间：
2021-09-09
影响因子：
5.4
通讯作者：
Saeed M
中科院分区：
文献类型：
--
作者：
Chen DY;Khan N;Close BJ;Goel RK;Blum B;Tavares AH;Kenney D;Conway HL;Ewoldt JK;Chitalia VC;Crossland NA;Chen CS;Kotton DN;Baker SC;Fuchs SY;Connor JH;Douam F;Emili A;Saeed M
SARS-CoV-2可以感染多个器官，包括肺、肠、肾、心、肝和脑。病毒如何在不同的细胞环境中导航并建立复制的分子细节尚不清楚。在这里，我们生成了一组表型多样化的sars - cov -2传染性人类细胞系，代表不同的身体器官，并对受病毒广泛影响的细胞蛋白和途径进行了纵向调查。这揭示了在SARS-CoV-2感染后，干扰素信号在不同细胞类型中普遍受到抑制。我们对包括永生化细胞和原代样心肌细胞在内的广泛细胞系统中的JAK-STAT通路进行了系统分析，发现SARS-CoV-2靶向近端通路组分，包括Janus激酶1 （JAK1）、酪氨酸激酶2 （Tyk2）和干扰素受体亚基1 (IFNAR1)，导致细胞对I型IFN脱敏。详细的机制研究表明，IFNAR1蛋白在SARS-CoV-2感染后发生泛素化。此外，JAK激酶的化学抑制增强了干细胞来源培养物的感染，表明病毒受益于抑制JAK- stat途径。这些发现表明，抑制干扰素信号是病毒广泛使用的逃避抗病毒先天免疫的机制，靶向免疫逃避的病毒介质可能有助于阻止COVID-19患者的病毒复制。SARS-CoV-2可以感染人体的各种器官，但病毒与这些器官之间的分子界面仍未被探索。在这项研究中，我们产生了一组来自不同身体器官的高度传染性的人类细胞系，并利用这些细胞来鉴定不同细胞类型中通常或明显被SARS-CoV-2破坏的细胞过程。其中一个普遍受损的过程是干扰素信号。对该途径在不同培养体系中的系统分析表明，SARS-CoV-2靶向近端JAK-STAT途径组分，通过泛素化破坏I型干扰素受体的稳定性，从而使感染细胞对I型干扰素产生抗性。这些发现阐明了SARS-CoV-2如何在存在播散性先天免疫反应的情况下继续在不同组织中繁殖。
SARS-CoV-2 can infect multiple organs, including lung, intestine, kidney, heart, liver, and brain. The molecular details of how the virus navigates through diverse cellular environments and establishes replication are poorly defined. Here, we generated a panel of phenotypically diverse, SARS-CoV-2-infectible human cell lines representing different body organs and performed longitudinal survey of cellular proteins and pathways broadly affected by the virus. This revealed universal inhibition of interferon signaling across cell types following SARS-CoV-2 infection. We performed systematic analyses of the JAK-STAT pathway in a broad range of cellular systems, including immortalized cells and primary-like cardiomyocytes, and found that SARS-CoV-2 targeted the proximal pathway components, including Janus kinase 1 (JAK1), tyrosine kinase 2 (Tyk2), and the interferon receptor subunit 1 (IFNAR1), resulting in cellular desensitization to type I IFN. Detailed mechanistic investigation of IFNAR1 showed that the protein underwent ubiquitination upon SARS-CoV-2 infection. Furthermore, chemical inhibition of JAK kinases enhanced infection of stem cell-derived cultures, indicating that the virus benefits from inhibiting the JAK-STAT pathway. These findings suggest that the suppression of interferon signaling is a mechanism widely used by the virus to evade antiviral innate immunity, and that targeting the viral mediators of immune evasion may help block virus replication in patients with COVID-19. IMPORTANCE SARS-CoV-2 can infect various organs in the human body, but the molecular interface between the virus and these organs remains unexplored. In this study, we generated a panel of highly infectible human cell lines originating from various body organs and employed these cells to identify cellular processes commonly or distinctly disrupted by SARS-CoV-2 in different cell types. One among the universally impaired processes was interferon signaling. Systematic analysis of this pathway in diverse culture systems showed that SARS-CoV-2 targets the proximal JAK-STAT pathway components, destabilizes the type I interferon receptor though ubiquitination, and consequently renders the infected cells resistant to type I interferon. These findings illuminate how SARS-CoV-2 can continue to propagate in different tissues even in the presence of a disseminated innate immune response.