Immune evasion strategy involving propionylation by the KSHV interferon regulatory factor 1 (vIRF1).
Immune evasion strategy involving propionylation by the KSHV interferon regulatory factor 1 (vIRF1).
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DOI：
10.1371/journal.ppat.1011324
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发表时间：
2023-04
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
翻译后修饰（ptm）是宿主抗病毒免疫应答和病毒免疫逃避的关键。在一组新的酰基化中，在组蛋白和非组蛋白中都检测到赖氨酸丙酰化（Kpr）。然而，蛋白质丙酰化是否发生在任何病毒蛋白中以及这种修饰是否调节病毒免疫逃避仍然是难以捉摸的。在这里，我们发现卡波西肉瘤相关疱疹病毒（KSHV）编码的病毒干扰素调节因子1 （vIRF1）可以在赖氨酸残基中丙酰化，这是有效抑制IFN-β产生和抗病毒信号传导所必需的。从机制上讲，vIRF1通过阻断SIRT6与泛素特异性肽酶10 （USP10）的相互作用来促进自身丙酸化，从而通过泛素-蛋白酶体途径导致其降解。此外，vIRF1丙酰化是其阻断IRF3-CBP/p300募集和抑制STING DNA传感通路的功能所必需的。一种sirt6特异性激活剂UBCS039可以挽救丙酰化virf1介导的IFN-β信号抑制。这些结果揭示了一种通过病毒蛋白丙酰化来逃避先天免疫的新机制。研究结果表明，参与病毒丙酰化的酶可能是预防病毒感染的潜在目标。传统的翻译后修饰在宿主抗病毒免疫应答和病毒免疫逃避中发挥着重要作用。最近发现了一组涉及赖氨酸丙酰化（Kpr）的非典型酰化反应。然而，Kpr修饰是否发生在病毒蛋白中或调节病毒免疫逃避尚不清楚。我们的研究发现卡波西肉瘤相关疱疹病毒（KSHV）编码的病毒干扰素调节因子1 （vIRF1）存在Kpr修饰以抑制IFN-β的产生。vIRF1通过阻断SIRT6与泛素特异性肽酶10 （USP10）的相互作用来促进自身丙酸化，从而通过泛素-蛋白酶体途径导致其降解。因此，目前的研究结果阐明了病毒免疫逃避策略的新机制，并为靶向Kpr和相关酶作为病毒感染的创新治疗策略提供了理论依据。
Post-translational modifications (PTMs) are essential for host antiviral immune response and viral immune evasion. Among a set of novel acylations, lysine propionylation (Kpr) has been detected in both histone and non-histone proteins. However, whether protein propionylation occurs in any viral proteins and whether such modifications regulate viral immune evasion remain elusive. Here, we show that Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded viral interferon regulatory factor 1 (vIRF1) can be propionylated in lysine residues, which is required for effective inhibition of IFN-β production and antiviral signaling. Mechanistically, vIRF1 promotes its own propionylation by blocking SIRT6’s interaction with ubiquitin-specific peptidase 10 (USP10) leading to its degradation via a ubiquitin-proteasome pathway. Furthermore, vIRF1 propionylation is required for its function to block IRF3-CBP/p300 recruitment and repress the STING DNA sensing pathway. A SIRT6-specific activator, UBCS039, rescues propionylated vIRF1-mediated repression of IFN-β signaling. These results reveal a novel mechanism of viral evasion of innate immunity through propionylation of a viral protein. The findings suggest that enzymes involved in viral propionylation could be potential targets for preventing viral infections. Conventional post-translational modifications play essential roles in host antiviral immune response and viral immune evasion. Recently, a set of atypical acylations involving lysine propionylation (Kpr) have been discovered. However, whether Kpr modification occurs in viral proteins or regulates viral immune evasion remain unknown. Our study uncovers Kpr modification exists in viral interferon regulatory factor 1 (vIRF1) encoded by Kaposi’s sarcoma-associated herpesvirus (KSHV) to inhibit IFN-β production. vIRF1 promotes its own propionylation by blocking SIRT6’s interaction with ubiquitin-specific peptidase 10 (USP10) leading to its degradation via a ubiquitin-proteasome pathway. Thus, the current findings illustrate a novel mechanism of viral immune evasion strategies and provide a rationale for targeting of Kpr and the associated enzymes as an innovative therapeutic strategy of virus infections.
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44.1
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