Wang Wenwen, Jia Mutian, Zhao Chunyuan, Yu Zhongxia, Song Hui, Qin Ying, Zhao Wei
Department of Immunology and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Shandong University, Jinan, Shandong, China.
State Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong, China.
Sci Adv. 2021 Mar 5;7(10). doi: 10.1126/sciadv.abe5877. Print 2021 Mar.
Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are major cytosolic RNA sensors and play crucial roles in initiating antiviral innate immunity. Furthermore, RLRs have been implicated in multiple autoimmune disorders. Thus, RLR activation should be tightly controlled to avoid detrimental effects. "DEAD-box RNA helicase 3, X-linked" (DDX3X) is a key adaptor in RLR signaling, but its regulatory mechanisms remain unknown. Here, we show that the E3 ubiquitin ligase RNF39 inhibits RLR pathways through mediating K48-linked ubiquitination and proteasomal degradation of DDX3X. Concordantly, deficiency enhances RNA virus-triggered innate immune responses and attenuates viral replication. Thus, our results uncover a previously unknown mechanism for the control of DDX3X activity and suggest RNF39 as a priming intervention target for diseases caused by aberrant RLR activation.
维甲酸诱导基因-I（RIG-I）样受体（RLRs）是主要的胞质RNA传感器，在启动抗病毒先天免疫中起关键作用。此外，RLRs还与多种自身免疫性疾病有关。因此，RLR的激活应受到严格控制，以避免产生有害影响。“X连锁的DEAD盒RNA解旋酶3”（DDX3X）是RLR信号传导中的关键衔接子，但其调控机制仍不清楚。在这里，我们表明E3泛素连接酶RNF39通过介导DDX3X的K48连接的泛素化和蛋白酶体降解来抑制RLR途径。相应地，RNF39缺陷增强了RNA病毒触发的先天免疫反应并减弱了病毒复制。因此，我们的结果揭示了一种以前未知的控制DDX3X活性的机制，并表明RNF39作为由异常RLR激活引起的疾病的启动干预靶点。
