Qian Yang,  Si-Yu Bai,  Lian-Feng Li,  Su Li,  Yuexiu Zhang,  Muhammad Munir,  Hua-Ji Qiu

J Virol. 2019 Jun 5. pii: JVI.00718-19. doi: 10.1128/JVI.00718-19

Abstract

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-I-mediated signaling through enhancing the K63-linked RIG-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.ImportanceHemoglobin, the most important oxygen-carrying protein, is involved in the regulation of innate immune responses. We have previously reported that the hemoglobin subunit beta (HB) of porcine exerts an antiviral ability through regulating the type I interferon production. However, the antiviral activities and the underlying mechanisms of HBs originated from other animals have been poorly understood. Here, we identified human HB (hHB) as a pleiotropic regulator of the replication of RNA viruses through regulating the RIG-I/MDA5-mediated signaling pathways. hHB enhances the RIG-I-mediated antiviral responses through promoting the RIG-I ubiquitination depending on the hHB-induced reactive oxygen species (ROS), while it blocks the MDA5-mediated antiviral signaling through suppressing the MDA5-dsRNA interaction. Our results contribute to understand the crucial roles of hHB in the regulation of the RIG-I/MDA5-mediated signaling pathways. We also provide a novel facet to the correlation of the intercellular redox state with the regulation of antiviral innate immunity.