Cao Chong, An Ran, Yu YueYang, Dai HaiYue, Qu ZheHui, Gao MingChun, Wang JunWei
Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
Front Microbiol. 2020 Jan 8;10:3040. doi: 10.3389/fmicb.2019.03040. eCollection 2019.
The infected cell protein 0 (BICP0) is an immediate early protein encoded by BHV-1, and its RING finger domain, which endows BICP0 with intrinsic E3 ubiquitin ligase activity, is common in all ICP0 proteins. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is one of the TRAF family members and is ubiquitously expressed in mammalian tissues. TRAF6 forms the MyD88-TRAF6-IRF7 complex and activates interferon induction in the TLR (Toll-like receptors) and the RLR (RIG-I-like receptor) pathway. Previous studies showed that BICP0 reduced IFN-β promoter activity by interacting with IRF7. In this study, we found that BICP0 promoted the K48-ubiquitination and degradation of TRAF6 through the ubiquitin proteasome system. The interaction between BICP0 and TRAF6 is a prerequisite for ubiquitination modification, and the 346-PAERQY-351 of BICP0 is indispensable. The motif mutation experiments showed that the tyrosine 351 of BICP0 is the key amino acid involved. Further studies demonstrated that BICP0 suppressed the NF-κB pathway via the interference of TRAF6. Moreover, degradation of TRAF6 protein influenced the K63-linked ubiquitination of IRF7 and activation of interferon promoter. Collectively, these findings indicate that the BICP0 protein suppresses the inflammation signaling and IFN production by K48-linked polyubiquitination of TRAF6 and may further clarify the immune evasion function of BICP0.
感染细胞蛋白0（BICP0）是由牛疱疹病毒1型（BHV-1）编码的一种立即早期蛋白，其环指结构域赋予BICP0内在的E3泛素连接酶活性，在所有ICP0蛋白中都很常见。肿瘤坏死因子受体相关因子6（TRAF6）是TRAF家族成员之一，在哺乳动物组织中普遍表达。TRAF6形成MyD88-TRAF6-IRF7复合物，并在Toll样受体（TLR）和RIG-I样受体（RLR）途径中激活干扰素诱导。先前的研究表明，BICP0通过与IRF7相互作用降低IFN-β启动子活性。在本研究中，我们发现BICP0通过泛素蛋白酶体系统促进TRAF6的K48-泛素化和降解。BICP0与TRAF6之间的相互作用是泛素化修饰的前提条件，BICP0的346-PAERQY-351是不可或缺的。基序突变实验表明，BICP0的酪氨酸351是关键氨基酸。进一步研究表明，BICP0通过干扰TRAF6抑制NF-κB途径。此外，TRAF6蛋白的降解影响IRF7的K63连接的泛素化和干扰素启动子的激活。总的来说，这些发现表明BICP0蛋白通过TRAF6的K48连接的多聚泛素化抑制炎症信号和IFN产生，并可能进一步阐明BICP0的免疫逃避功能。
