1. Mammalian reovirus µ1 protein attenuates RIG-I and MDA5-mediated signaling transduction by blocking IRF3 phosphorylation and nuclear translocation.
- Author
-
Wu B, Li D, Bai H, Mo R, Li H, Xie J, Zhang X, Yang Y, Li H, Idris A, Li X, and Feng R
- Subjects
- Animals, Humans, Active Transport, Cell Nucleus, Cell Nucleus metabolism, HEK293 Cells, Immunity, Innate immunology, Interferon-beta metabolism, Interferon-beta immunology, Phosphorylation, Protein Serine-Threonine Kinases, Reoviridae Infections immunology, Viral Proteins metabolism, DEAD Box Protein 58 metabolism, Interferon Regulatory Factor-3 metabolism, Interferon-Induced Helicase, IFIH1 metabolism, Interferon-Induced Helicase, IFIH1 genetics, Orthoreovirus, Mammalian immunology, Orthoreovirus, Mammalian physiology, Receptors, Immunologic, Signal Transduction immunology, Capsid Proteins metabolism
- 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF