哺乳动物呼肠孤病毒(MRV)是一种无包膜,基因分段双链RNA(dsRNA)病毒。它是一种重要的人畜共患病原体,感染许多作为自然宿主的哺乳动物和脊椎动物,并引起呼吸道和消化道疾病。有研究报道,先天免疫细胞质RNA敏感RIG样受体(RLR)信号通路中的RIG-I和MDA5可以识别MRV的dsRNA并促进抗病毒I型干扰素(IFN)反应。然而,许多MRV编码蛋白逃避宿主先天免疫应答的机制尚不清楚.这里,我们表明外源μ1蛋白在体外促进MRV的增殖,而shRNA对MRVμ1蛋白表达的敲低可以损害MRV的增殖。具体来说,μ1蛋白抑制MRV或聚(I:C)诱导的IFN-β表达,和减弱MRV感染期间RIG-I/MDA5介导的信号轴转导。重要的是,我们发现μ1蛋白显著降低MDA5、RIG-I、MAVS,TBK1,IRF3(5D),并降解外源MDA5,RIG-I,MAVS,TBK1和IRF3通过蛋白酶体和溶酶体途径。此外,我们表明μ1蛋白可以与MDA5、RIG-I、MAVS,TBK1和IRF3,并通过阻断IRF3的磷酸化和核易位来减弱RIG-I/MDA5介导的信号传导级联。总之,我们的研究结果表明,MRV外壳蛋白μ1是拮抗RLRs信号级联的关键因素,为有效预防和治疗MRV感染提供了新的策略。
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.