Study On The Pleiotropic Mechanism Of Human Hemoglobin Subunit Beta Regulating The RIG-?/MDA5-mediated Antiviral Innate Immune Responses

Hemoglobin is an important oxygen-carrying protein and plays crucial roles in establishing host resistance against pathogens and regulating innate immune responses.The hemoglobin subunit beta(HB)is an essential component of hemoglobin,and we have previously demonstrated that the antiviral role of the porcine HB(pHB)is mediated by promoting the type I interferon pathways.Thus,considering the high homology between human HB(hHB)and pHB,we hypothesized that hHB also play an important role in the antiviral innate immunity.In this study,we characterized hHB as a regulatory factor for the replication of RNA viruses by differentially regulating the RIG-I-and MDA5-mediated antiviral signaling pathways.Furthermore,we showed that hHB directly inhibited the MDA5-mediated signaling through reducing the MDA5-dsRNA affinity.Additionally,hHB required hHB-induced reactive oxygen species to promote the RIG-1-mediated signaling through enhancing the K63-linked RI[G-I ubiquitination.Taken together,our findings suggest that hHB is a pleiotropic regulator of the RIG-I/MDA5-mediated antiviral responses and further highlight the importance of intercellular microenvironment including redox state in regulating the antiviral innate immune responses.