RNF39 mediates K48-linked ubiquitination of DDX3X and inhibits RLR-dependent antiviral immunity

  • Sci Adv. 2021 Mar 5;7(10):eabe5877. doi: 10.1126/sciadv.abe5877.
Wenwen Wang  1  2 ,  Mutian Jia  1  2 ,  Chunyuan Zhao  1  2  3 ,  Zhongxia Yu  1  2 ,  Hui Song  1  2 ,  Ying Qin  1  2 ,  Wei Zhao  4  2
Affiliations
  • 1. 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.
  • 2. State Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong, China.
  • 3. Department of Cell Biology, School of Basic Medical Science, Shandong University, Jinan, Shandong, China.
  • 4. 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. [email protected].
PMID: 33674311 DOI: 10.1126/sciadv.abe5877
Abstract

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, Rnf39 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.