State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Department of Physiology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Rep. 2022 Jul 26;40(4):111143. doi: 10.1016/j.celrep.2022.111143.
Host antiviral immunity suffers strong pressure from rapidly evolving viruses. Identifying host antiviral immune mechanisms has profound implications for developing antiviral strategies. Here, we uncover an essential role for the tumor suppressor Ras-association domain family (RASSF) in Drosophila antiviral response. Loss of dRassf in fat body leads to increased vulnerability to viral infection and impaired Imd pathway activation accompanied by detrimental JAK/STAT signaling overactivation. Mechanistically, dRASSF protects TAK1, a key kinase of Imd pathway, from inhibition by the STRIPAK PP2A phosphatase complex. Activated Imd signaling then employs the effector Relish to interfere with the dimerization of JAK/STAT transmembrane receptor Domeless, therefore preventing excessive JAK/STAT signaling. Moreover, we find that RASSF and STRIPAK PP2A complex are also involved in antiviral response in human cell lines. Our study identifies an important role for RASSF in antiviral immunity and elucidates a dRASSF-STRIPAK-Imd-JAK/STAT signaling axis that ensures proper antiviral responses in Drosophila.
宿主抗病毒免疫受到快速进化病毒的强大压力。鉴定宿主抗病毒免疫机制对开发抗病毒策略具有深远意义。在这里，我们揭示了肿瘤抑制因子 Ras-association domain family (RASSF) 在果蝇抗病毒反应中的重要作用。脂肪体中 dRassf 的缺失导致对病毒感染的易感性增加，并损害了 Imd 途径的激活，同时伴随着有害的 JAK/STAT 信号过度激活。在机制上，dRASSF 保护了 Imd 途径的关键激酶 TAK1，使其免受 STRIPAK PP2A 磷酸酶复合物的抑制。激活的 Imd 信号随后利用效应因子 Relish 干扰 JAK/STAT 跨膜受体 Domeless 的二聚化，从而防止过度的 JAK/STAT 信号。此外，我们发现 RASSF 和 STRIPAK PP2A 复合物也参与了人细胞系中的抗病毒反应。我们的研究确定了 RASSF 在抗病毒免疫中的重要作用，并阐明了 dRASSF-STRIPAK-Imd-JAK/STAT 信号轴，确保了果蝇中适当的抗病毒反应。
