Pseudorabies virus (PRV) has evolved various immune evasion mechanisms that target host antiviral immune responses. However, it is unclear whether and how PRV encoded proteins modulate the cGAS-STING axis for immune evasion. Here, we show that PRV tegument protein UL13 inhibits STING-mediated antiviral signaling via regulation of STING stability. Mechanistically, UL13 interacts with the CDN domain of STING and recruits the E3 ligase RING-finger protein 5 (RNF5) to promote K27-/K29-linked ubiquitination and degradation of STING. Consequently, deficiency of RNF5 enhances host antiviral immune responses triggered by PRV infection. In addition, mutant PRV lacking UL13 impaired in antagonism of STING-mediated production of type I IFNs and shows attenuated pathogenicity in mice. Our findings suggest that PRV UL13 functions as an antagonist of IFN signaling via a novel mechanism by targeting STING to persistently evade host antiviral responses.

中文翻译：

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伪狂犬病病毒外皮蛋白 UL13 募集 RNF5 以抑制 STING 介导的抗病毒免疫。

伪狂犬病病毒 (PRV) 已经进化出多种针对宿主抗病毒免疫反应的免疫逃避机制。然而，尚不清楚 PRV 编码的蛋白质是否以及如何调节 cGAS-STING 轴以进行免疫逃避。在这里，我们表明 PRV 外皮蛋白 UL13 通过调节 STING 稳定性来抑制 STING 介导的抗病毒信号传导。从机制上讲，UL13 与 STING 的 CDN 结构域相互作用并募集 E3 连接酶环指蛋白 5 (RNF5) 以促进 K27-/K29 连接的 STING 泛素化和降解。因此，RNF5 的缺乏增强了由 PRV 感染引发的宿主抗病毒免疫反应。此外，缺乏 UL13 的突变 PRV 对 STING 介导的 I 型 IFN 产生的拮抗作用受损，并在小鼠中表现出减弱的致病性。