RESUMEN
Innate immunity to nucleic acids forms the backbone for anti-viral immunity and several inflammatory diseases. Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type I interferon (IFN-I). TRAF3-interacting protein 3 (TRAF3IP3, T3JAM) is essential for T and B cell development. It is also well-expressed by myeloid cells, where its role is unknown. Here we report that TRAF3IP3 suppresses cytosolic poly(I:C), 5'ppp-dsRNA, and vesicular stomatitis virus (VSV) triggers IFN-I expression in overexpression systems and Traf3ip3-/- primary myeloid cells. The mechanism of action is through the interaction of TRAF3IP3 with endogenous TRAF3 and TBK1. This leads to the degradative K48 ubiquitination of TBK1 via its K372 residue in a DTX4-dependent fashion. Mice with myeloid-specific gene deletion of Traf3ip3 have increased RNA virus-triggered IFN-I production and reduced susceptibility to virus. These results identify a function of TRAF3IP3 in the regulation of the host response to cytosolic viral RNA in myeloid cells.
Asunto(s)
Proteínas Portadoras/genética , Regulación de la Expresión Génica , Interferón Tipo I/genética , Proteínas de la Membrana/genética , Células Mieloides/metabolismo , Proteínas Serina-Treonina Quinasas/genética , ARN Viral/genética , Animales , Proteínas Portadoras/metabolismo , Línea Celular , Células Cultivadas , Chlorocebus aethiops , Citosol/metabolismo , Citosol/virología , Células HEK293 , Células HeLa , Humanos , Interferón Tipo I/metabolismo , Células Jurkat , Lisina/genética , Lisina/metabolismo , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células Mieloides/virología , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Viral/metabolismo , Células THP-1 , Ubiquitinación , Células Vero , Virus de la Estomatitis Vesicular Indiana/genética , Virus de la Estomatitis Vesicular Indiana/fisiologíaRESUMEN
BACKGROUND: Major histocompatibility complex (MHC) antigenic complexes trigger allogeneic T-cell responses and allograft rejection. MHC class II and related antigen processing genes, such as invariant chain (Ii) and H2-DM accessory molecules, are controlled by the master transcriptional regulator, class II transactivator (CIITA). CIITA also up-regulates MHC class I gene expression in vitro. Thus, disruption of a single factor, namely CIITA, represents an ideal strategy for reducing transplant rejection. METHODS: We studied the immunological advantages of transplanting CIITA deficient hearts into mismatched recipients in comparison to wild-type (B6) allografts or MHC class II-deficient (Abeta ) hearts. RESULTS: Elimination of CIITA greatly enhanced graft survival (median survival time [MST] 36 days) over the survival of wild-type (MST 9 days) and even over Abeta (MST 20 days) cardiac grafts. This was accompanied by greatly reduced mixed lymphocyte reactivity and in vivo antigen priming capacity. Analyses for CD4, CD8, and other inflammatory cells, plus cytotoxic T-cell activity and MHC class I specific alloantibody production, did not reveal significant differences in CIITA allograft tissues. Some cytokines that may support immunosuppression, such as transforming growth factor (TGF)-beta, were increased in mice receiving either Abeta or CIITA cardiac grafts. CONCLUSIONS: We conclude that disruption of CIITA function plays a beneficial role in preventing normal allogeneic T-cell responses. Even though inflammatory cells are present in CIITA allografts, the dramatic prolongation in allograft survival of CIITA hearts as compared with wild-type grafts provides a foundation for designing molecular therapies to interfere with MHC class II function and thereby reduce transplantation rejection.