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

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Mammalian reovirus (MRV) is a zoonotic pathogen causing respiratory and digestive diseases.
• The RIG-like receptor (RLR) pathway, involving RIG-I and MDA5, senses viral dsRNA and triggers innate immune responses.
• Mechanisms of MRV immune evasion are not fully understood.

Purpose of the Study:

• To investigate the role of MRV outer capsid protein μ1 in viral proliferation and host innate immune evasion.
• To elucidate the molecular mechanisms by which μ1 antagonizes the RLR signaling pathway.

Main Methods:

• In vitro studies using MRV and poly(I:C) to assess viral proliferation and IFN-β expression.
• shRNA-mediated knockdown of μ1 protein expression.
• Analysis of RLR signaling components (MDA5, RIG-I, MAVS, TBK1, IRF3) and their degradation.
• Co-immunoprecipitation assays to detect protein interactions.
• Western blotting to assess protein phosphorylation and nuclear translocation.

Main Results:

• Exogenous μ1 protein promoted MRV proliferation in vitro; μ1 knockdown impaired MRV replication.
• μ1 inhibited MRV or poly(I:C)-induced IFN-β expression and attenuated RIG-I/MDA5 signaling.
• μ1 protein degraded MDA5, RIG-I, MAVS, TBK1, and IRF3 via proteasomal and lysosomal pathways.
• μ1 physically interacted with MDA5, RIG-I, MAVS, TBK1, and IRF3, blocking IRF3 phosphorylation and nuclear translocation.

Conclusions:

• MRV outer capsid protein μ1 is a key antagonist of the RLR signaling pathway.
• μ1 inhibits innate antiviral responses by degrading key signaling proteins and blocking IRF3 activation.
• These findings offer potential strategies for preventing and treating MRV infections.