As the most primordial signaling pathway in animal physiology, the Hippo pathway and innate immunity play crucial roles not only in sensing cellular conditions or infections, but also in various metabolite homeostasis and tumorigenesis. However, the correlation between cellular homeostasis and antiviral defense is not well understood. The core kinase LATS1/2, could either enhance or inhibit the anti-tumor immunity in different cellular contexts. In this study, we found that LATS2 can interact with PQBP1, the co-factor of cGAS, thus enhanced the cGAS-STING mediated innate immune response to HIV-1 challenge. LATS2 was observed to upregulate type-I interferon (IFN-I) and cytokines in response to HIV-1 reverse-transcribed DNA and inhibited HIV-1 infection. Due to the involvement of PQBP1, the function of LATS2 in regulating cGAS activity is not relying on the downstream YAP/TAZ as that in the canonical Hippo pathway. The related kinase activity of LATS2 was verified, and the potential phosphorylation site of PQBP1 was identified. Our study established a novel connection between Hippo signaling and innate immunity, thus may provide new potential intervention target on antiviral therapeutics.

作为动物生理学中最原始的信号通路，Hippo 通路和先天免疫不仅在感知细胞状况或感染方面发挥着至关重要的作用，而且在各种代谢物稳态和肿瘤发生中也起着至关重要的作用。然而，细胞稳态与抗病毒防御之间的相关性尚不清楚。核心激酶 LATS1/2 可以增强或抑制不同细胞环境中的抗肿瘤免疫力。在这项研究中，我们发现 LATS2 可以与 cGAS 的辅助因子 PQBP1 相互作用，从而增强 cGAS-STING 介导的对 HIV-1 攻击的先天免疫反应。观察到 LATS2 上调 I 型干扰素 (IFN-I) 和细胞因子以响应 HIV-1 逆转录 DNA 并抑制 HIV-1 感染。由于PQBP1的参与，LATS2 调节 cGAS 活性的功能并不像典型的 Hippo 通路那样依赖于下游 YAP/TAZ。验证了 LATS2 的相关激酶活性，并确定了 PQBP1 的潜在磷酸化位点。我们的研究在 Hippo 信号和先天免疫之间建立了一种新的联系，因此可能为抗病毒治疗提供新的潜在干预靶点。