Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Biomedical Sciences, Shandong University, 250012 Jinan, Shandong, People's Republic of China.
Department of Pathogenic Biology, School of Biomedical Sciences, Shandong University, 250012 Jinan, Shandong, People's Republic of China; and.
J Immunol. 2021 Apr 15;206(8):1832-1843. doi: 10.4049/jimmunol.2001253. Epub 2021 Mar 31.
CARD9 is an essential adaptor protein in antifungal innate immunity mediated by C-type lectin receptors. The activity of CARD9 is critically regulated by ubiquitination; however, the deubiquitinases involved in CARD9 regulation remain incompletely understood. In this study, we identified ovarian tumor deubiquitinase 1 (OTUD1) as an essential regulator of CARD9. OTUD1 directly interacted with CARD9 and cleaved polyubiquitin chains from CARD9, leading to the activation of the canonical NF-κB and MAPK pathway. OTUD1 deficiency impaired CARD9-mediated signaling and inhibited the proinflammatory cytokine production following fungal stimulation. Importantly, mice were more susceptible to fungal infection than wild-type mice in vivo. Collectively, our results identify OTUD1 as an essential regulatory component for the CARD9 signaling pathway and antifungal innate immunity through deubiquitinating CARD9.
CARD9 是 C 型凝集素受体介导的抗真菌固有免疫中的一种必需衔接蛋白。CARD9 的活性受到泛素化的严格调控；然而，参与 CARD9 调节的去泛素化酶仍不完全清楚。在这项研究中，我们鉴定出卵巢肿瘤去泛素化酶 1（OTUD1）是 CARD9 的一个必需调节因子。OTUD1 直接与 CARD9 相互作用，并从 CARD9 上切割多聚泛素链，导致经典的 NF-κB 和 MAPK 途径的激活。OTUD1 缺陷抑制了 CARD9 介导的信号转导，并抑制了真菌刺激后的促炎细胞因子产生。重要的是，OTUD1 缺陷小鼠在体内对真菌感染的敏感性高于野生型小鼠。总之，我们的研究结果表明，OTUD1 通过去泛素化 CARD9 作为 CARD9 信号通路和抗真菌固有免疫的必需调节成分。
