Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion.
Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion.
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HIV-1蛋白酶对储罐结合激酶1的切割触发病毒先天免疫逃避。
DOI：
10.3389/fmicb.2021.643407
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发表时间：
2021
影响因子：
5.2
通讯作者：
Ryo A
中科院分区：
文献类型：
--
作者：
Jeremiah SS;Miyakawa K;Matsunaga S;Nishi M;Kudoh A;Takaoka A;Sawasaki T;Ryo A
I型干扰素（IFN-1）是先天免疫系统对抗病毒感染的主要防御。人类免疫缺陷病毒-1（HIV-1）已经进化出几种方式来抑制或逃避宿主的先天免疫，以便生存和复制以维持感染。IFN-I的抑制是HIV-1用于阻止其清除的多种逃避策略之一。还观察到有助于病毒成熟的HIV-1蛋白酶切割宿主细胞蛋白激酶。在这项研究中，我们使用AlphaScreen分析对人类激酶文库进行了全面的筛选，并确定TANK结合激酶-1（TBK 1）被HIV-1蛋白酶（PR）切割。我们证明，PR裂解TBK 1未能磷酸化IFN调节因子3（IRF 3），从而降低IFN-Ⅰ启动子活性，并进一步揭示，PR介导的抑制IFN-Ⅰ可以抵消蛋白酶抑制剂（PI）在体外。我们还发现，HIV-1 PR的突变使PI产生耐药性，从而降低了酶切割TBK 1的能力。这项研究的结果揭示了HIV-1 PR活性与病毒逃避先天免疫之间的直接联系，其可能的生理相关性有待确定。
Type-I interferons (IFN-I) are the innate immune system’s principal defense against viral infections. Human immunodeficiency virus-1 (HIV-1) has evolved several ways to suppress or evade the host’s innate immunity in order to survive and replicate to sustain infection. Suppression of IFN-I is one among the multiple escape strategies used by HIV-1 to prevent its clearance. HIV-1 protease which helps in viral maturation has also been observed to cleave host cellular protein kinases. In this study we performed a comprehensive screening of a human kinase library using AlphaScreen assay and identified that TANK binding kinase-1 (TBK1) was cleaved by HIV-1 protease (PR). We demonstrate that PR cleaved TBK1 fails to phosphorylate IFN regulatory factor 3 (IRF3), thereby reducing the IFN-I promoter activity and further reveal that the PR mediated suppression of IFN-I could be counteracted by protease inhibitors (PI) in vitro. We have also revealed that mutations of HIV-1 PR that confer drug resistance to PIs reduce the enzyme’s ability to cleave TBK1. The findings of this study unearth a direct link between HIV-1 PR activity and evasion of innate immunity by the virus, the possible physiological relevance of which warrants to be determined.
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影响因子：
2.9
作者：
de Vera IM;Smith AN;Dancel MC;Huang X;Dunn BM;Fanucci GE
通讯作者：
Fanucci GE
影响因子：
3.3
作者：
Kudoh A;Takahama S;Sawasaki T;Ode H;Yokoyama M;Okayama A;Ishikawa A;Miyakawa K;Matsunaga S;Kimura H;Sugiura W;Sato H;Hirano H;Ohno S;Yamamoto N;Ryo A
通讯作者：
Ryo A
影响因子：
3.8
作者：
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通讯作者：
Wang, Chin-Tien
影响因子：
3.7
作者：
Okumura, Atsushi;Alce, Tim;Pitha, Paula M.
通讯作者：
Pitha, Paula M.
影响因子：
5.4
作者：
Palermo, Enrico;Acchioni, Chiara;Hiscott, John
通讯作者：
Hiscott, John