RNF144B negatively regulates antiviral immunity by targeting MDA5 for autophagic degradation

  • EMBO Rep. 2024 Oct;25(10):4594-4624. doi: 10.1038/s44319-024-00256-w.
Guoxiu Li  #  1  2  3 ,  Jing Zhang  #  4  5 ,  Zhixun Zhao  1  3 ,  Jian Wang  1  3 ,  Jiaoyang Li  1  3 ,  Weihong Xu  1  3 ,  Zhanding Cui  1  3 ,  Pu Sun  1  3 ,  Hong Yuan  1  3 ,  Tao Wang  1  3 ,  Kun Li  1  3 ,  Xingwen Bai  1  3 ,  Xueqing Ma  1  3 ,  Pinghua Li  1  3 ,  Yuanfang Fu  1  3 ,  Yimei Cao  1  3 ,  Huifang Bao  1  3 ,  Dong Li  1  3 ,  Zaixin Liu  1  3 ,  Ning Zhu  1  3 ,  Lijie Tang  6 ,  Zengjun Lu  7  8
Affiliations
  • 1. State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China.
  • 2. Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China.
  • 3. Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, 730046, China.
  • 4. State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China. [email protected].
  • 5. Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, 730046, China. [email protected].
  • 6. Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China. [email protected].
  • 7. State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, China. [email protected].
  • 8. Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, 730046, China. [email protected].
  • # Contributed equally.
PMID: 39285245 DOI: 10.1038/s44319-024-00256-w
Abstract

As a RIG-I-like Receptor, MDA5 plays a critical role in Antiviral innate immunity by acting as a cytoplasmic double-stranded RNA sensor capable of initiating type I interferon pathways. Here, we show that RNF144B specifically interacts with MDA5 and promotes K27/K33-linked polyubiquitination of MDA5 at lysine 23 and lysine 43, which promotes autophagic degradation of MDA5 by p62. Rnf144b deficiency greatly promotes IFN production and inhibits EMCV replication in vivo. Importantly, Rnf144b-/- mice has a significantly higher overall survival rate than wild-type mice upon EMCV Infection. Collectively, our results identify RNF144B as a negative regulator of innate Antiviral response by targeting CARDs of MDA5 and mediating autophagic degradation of MDA5.

Keywords
E3 Ligase; Innate Immunity; MDA5; RNF144B; Type I Interferon.
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