SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species.
SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species.
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DOI：
10.1080/22221751.2020.1870414
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发表时间：
2021-12
影响因子：
13.2
通讯作者：
Gambin Y
中科院分区：
文献类型：
--
作者：
Moustaqil M;Ollivier E;Chiu HP;Van Tol S;Rudolffi-Soto P;Stevens C;Bhumkar A;Hunter DJB;Freiberg AN;Jacques D;Lee B;Sierecki E;Gambin Y
SARS-CoV-2的基因组编码两种病毒蛋白酶（NSP 3/papain-like protease和NSP 5/3C-like protease），其负责在复制期间切割病毒多聚蛋白。在这里，我们发现了SARS-CoV-2的NSP 3和NSP 5蛋白酶的新功能，证明它们可以直接切割参与宿主先天免疫反应的蛋白质。我们鉴定了3种被NSP 3或NSP 5特异性和选择性切割的蛋白：IRF-3，NLRP 12和TAB 1。NSP 3对IRF 3的直接切割可以解释在SARS-CoV-2感染期间观察到的I型IFN反应减弱，而NSP 5介导的NLRP 12和TAB 1切割指向COVID-19患者中观察到的细胞因子产生和炎症反应增强的分子机制。我们证明，在小鼠NLRP 12蛋白中，在我们的体外测定中，识别位点之一没有被切割。我们推动了IRF-3和NLRP 12同源物的比较比对，并表明IRF-3和NLRP 12中同源切割基序的缺乏或存在可能有助于猫和老虎的疾病表现。我们的发现为深入研究COVID-19的病理生理学提供了一个解释框架。
The genome of SARS-CoV-2 encodes two viral proteases (NSP3/papain-like protease and NSP5/3C-like protease) that are responsible for cleaving viral polyproteins during replication. Here, we discovered new functions of the NSP3 and NSP5 proteases of SARS-CoV-2, demonstrating that they could directly cleave proteins involved in the host innate immune response. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of cytokines and inflammatory response observed in COVID-19 patients. We demonstrate that in the mouse NLRP12 protein, one of the recognition site is not cleaved in our in-vitro assay. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for indepth studies into the pathophysiology of COVID-19.
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影响因子：
5.6
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
Chen, Zhongbin
DOI：
10.1073/pnas.0708616105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Jeru, I.;Duquesnoy, P.;Amselem, S.
通讯作者：
Amselem, S.
影响因子：
4.8
作者：
Ge, BX;Xiong, XS;Han, JH
通讯作者：
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