Cyclic GMP-AMP synthase (cGAS) is an essential sensor of cytosolic DNA and critically mediates innate immune responses and autoimmunity. Modulating the activity and stability of cGAS provides potential strategies for treating viral or autoimmune diseases. Here, we report that ubiquitin-specific protease 29 (USP29) deubiquitinates and stabilizes cGAS and promotes cellular antiviral responses and autoimmunity. Knockdown or knockout of USP29 severely impairs Herpes simplex virus 1 (HSV-1)- or cytosolic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Consistently, Usp29^m/m mice produce decreased type I IFNs and proinflammatory cytokines after HSV-1 infection and are hypersensitive to HSV-1 infection compared to the wild-type littermates. In addition, genetic ablation of USP29 in Trex1^−/− mice eliminated the detectable pathological and molecular autoimmune phenotypes. Mechanistically, USP29 constitutively interacts with cGAS, deconjugates K48-linked polyubiquitin chains from cGAS and stabilizes cGAS in uninfected cells or after HSV-1 infection. Reconstitution of cGAS into Usp29^−/− cells fully rescues type I IFN induction and cellular antiviral responses after HSV-1 infection. Our findings thus reveal a critical role of USP29 in the innate antiviral responses against DNA viruses and autoimmune diseases and provide insight into the regulation of cGAS.

环 GMP-AMP 合酶 (cGAS) 是细胞溶质 DNA 的重要传感器，并且关键地介导先天免疫反应和自身免疫。调节 cGAS 的活性和稳定性为治疗病毒或自身免疫性疾病提供了潜在的策略。在这里，我们报告泛素特异性蛋白酶 29 (USP29) 去泛素化和稳定 cGAS 并促进细胞抗病毒反应和自身免疫。USP29 的敲低或敲除会严重损害单纯疱疹病毒 1 (HSV-1) 或胞质 DNA 诱导的 I 型干扰素 (IFN) 和促炎细胞因子的表达。一贯地，USP29 ^m/m与野生型同窝小鼠相比，小鼠在 HSV-1 感染后产生的 I 型干扰素和促炎细胞因子减少，并且对 HSV-1 感染过敏。此外，Trex1 ^-/-小鼠中 USP29 的基因消融消除了可检测的病理和分子自身免疫表型。从机制上讲，USP29 与 cGAS 组成型相互作用，从 cGAS 中解离 K48 连接的多聚泛素链，并在未感染细胞或 HSV-1 感染后稳定 cGAS。将 cGAS 重组为Usp29 ^-/-细胞完全挽救 HSV-1 感染后 I 型干扰素诱导和细胞抗病毒反应。因此，我们的研究结果揭示了 USP29 在针对 DNA 病毒和自身免疫性疾病的先天抗病毒反应中的关键作用，并提供了对 cGAS 调控的深入了解。