Inducible ATP1B1 Activates Antiviral Innate Immune Responses By Targeting TRAF6 And TRAF5

The natural immune response is the key step of host defense,in which the anti-virus response of interferon is very important in host immune response,and plays a role in controlling virus infection.The human ATPase Na~+/K~+transporter subunitβ1,namely ATP1B1,is aβsubunit encoding Na~+/K~+-ATPase,belonging to the Na~+/K~+and H~+/K~+ATPaseβchain protein family,and belongs to the Na~+/K~+-ATPase subfamily.Some reports show that virus infection can induce the expression of some proteins in ATPase family,but there is little research on the relationship between the virus and ATP1B1.We reported for the first time that the transcription and translation levels of ATP1B1 were significantly increased after DNA and RNA viruses(HSV,IAV,VSV,EV71 and Se V)infection.We found that overexpression of ATP1B1 in cells can significantly inhibit the replication of IAV,VSV,EV71 and HSV,and promoted the production of interferons,pro-inflammatory factors and interferon stimulated genes.Knockdown of ATP1B1 by specific sh RNA had the opposite effects.Upon viral infection,ATP1B1 was induced,and interacted with TRAF6 and TRAF3,and potentiated the K63 ubiquitination of these proteins,leading to increased phosphorylation of downstream molecules including TGF-β-activated kinase 1(TAK1),TANK-binding kinase 1(TBK1)and their downstream signal proteins,eventually promoted the nuclear import of p50,p65 and IRF3/IRF7 and led to the activation of NF-κB and IRF3/7,which induced the abundant expression of interferon and proinflammatory cytokines.These results reveal a previously unrecognized role of ATP1B1 in antiviral innate immunity,and suggest a novel mechanism for the induction of IFNs and pro-inflammatory cytokines during viral infection.