Mammalian reovirus µ1 protein attenuates RIG-I and MDA5-mediated signaling transduction by blocking IRF3 phosphorylation and nuclear translocation

Bei Wu; Dianyu Li; Huisheng Bai; Rongqian Mo; Hongshan Li; Jingying Xie; Xiangbo Zhang; Yanmei Yang; Huixia Li; Adi Idris; Xiangrong Li; Ruofei Feng

doi:10.1016/j.molimm.2024.04.010

Mammalian reovirus µ1 protein attenuates RIG-I and MDA5-mediated signaling transduction by blocking IRF3 phosphorylation and nuclear translocation

Mol Immunol. 2024 Apr 24:170:131-143. doi: 10.1016/j.molimm.2024.04.010. Online ahead of print.

Authors

Bei Wu¹, Dianyu Li¹, Huisheng Bai¹, Rongqian Mo¹, Hongshan Li¹, Jingying Xie¹, Xiangbo Zhang¹, Yanmei Yang¹, Huixia Li², Adi Idris³, Xiangrong Li⁴, Ruofei Feng⁵

Affiliations

¹ Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; College of Life science and Engineering, Northwest Minzu University, Lanzhou, China.
² Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.
³ School of Biomedical Sciences, Centre for Immunology and Infection Control, Herston, Queensland University of Technology, China; Menzies Health Institute Queensland, School of Pharmacy and Medical Science, Griffith University, Southport, Queensland, Australia.
⁴ Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou, China. Electronic address: lixiangrong@xbmu.edu.cn.
⁵ Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China; Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou, China. Electronic address: fengruofei@xbmu.edu.cn.

PMID: 38663254
DOI: 10.1016/j.molimm.2024.04.010

Abstract

Mammalian reovirus (MRV) is a non-enveloped, gene segmented double-stranded RNA (dsRNA) virus. It is an important zoonotic pathogen that infects many mammals and vertebrates that act as natural hosts and causes respiratory and digestive tract diseases. Studies have reported that RIG-I and MDA5 in the innate immune cytoplasmic RNA-sensing RIG-like receptor (RLR) signaling pathway can recognize dsRNA from MRV and promote antiviral type I interferon (IFN) responses. However, the mechanism by which many MRV-encoded proteins evade the host innate immune response remains unclear. Here, we show that exogenous μ1 protein promoted the proliferation of MRV in vitro, while knockdown of MRV μ1 protein expression by shRNA could impair MRV proliferation. Specifically, μ1 protein inhibited MRV or poly(I:C)-induced IFN-β expression, and attenuated RIG-I/MDA5-mediated signaling axis transduction during MRV infection. Importantly, we found that μ1 protein significantly decreased IFN-β mRNA expression induced by MDA5, RIG-I, MAVS, TBK1, IRF3(5D), and degraded the protein expression of exogenous MDA5, RIG-I, MAVS, TBK1 and IRF3 via the proteasomal and lysosomal pathways. Additionally, we show that μ1 protein can physically interact with MDA5, RIG-I, MAVS, TBK1, and IRF3 and attenuate the RIG-I/MDA5-mediated signaling cascades by blocking the phosphorylation and nuclear translocation of IRF3. In conclusion, our findings reveal that MRV outer capsid protein μ1 is a key factor in antagonizing RLRs signaling cascades and provide new strategies for effective prevention and treatment of MRV infection.

Keywords: IRF3; MDA5; Mammalian reovirus; RIG-I; µ1.