Inducible TAP1 Negatively Regulates The Antiviral Innate Immune Response By Targeting The TAK1 Complex

The innate immune response is critical for host defense and must be tightly controlled,but the molecular mechanisms responsible for its negative regulation are not yet completely understood.Here,we report that transporter 1,ATP-binding cassette(TAP1),a virus-inducible endoplasmic reticulum(ER)-associated protein,negatively regulated the virus-triggered immune response.In this study,we observed upregulated expression of TAP1 following virus infection in human lung epithelial cells(A549),THP-1 monocytes,HeLa cells and Vero cells.The overexpression of TAP1 enhanced virus replication by inhibiting the virus-triggered activation of nuclear factor kappa B(NF-?B)signaling and the production of interferons(IFNs),interferon-stimulated genes(ISGs)and proinflammatory cytokines.TAP1 depletion had the opposite effect.In response to virus infection,TAP1 interacted with the transforming growth factor-?-activated kinase(TAK)1 complex and impaired the phosphorylation of TAK1,subsequently suppressing the phosphorylation of the I?B kinase(IKK)complex and NF-?B inhibitor-a(I?B?)as well as NF-?B nuclear translocation.TAP1 is a member of the MDR/TAP subfamily of ATP-binding cassette(ABC)transporters.TAP1 together with TAP2,forms the TAP complex,which resides on the ER membrane and is responsible for the pumping of degraded cytosolic antigenic peptides across the endoplasmic reticulum into the membrane-bound compartment for association with MHC class I molecules.Several functions of TAP1 have been described,which have mainly focused on antigen presentation and adaptive immunity.However,its role in innate immune signaling in response to viral infection has never been established.In this study,our results describe a previously unrecognized role of TAP1 as a virus-inducible negative regulator of innate immunity by targeting the TAK1-TAB complex and blocking TAK1 phosphorylation.