Our long-term goals are to investigate the molecular mechanisms of inflammation and innate immunity and identify molecular targets for drug development against inflammatory and infectious diseases. TNF, IL-1 and Toll-like receptors (TLRs) are critically involved in inflammation and innate immunity through activation of the transcription factor NF-KAPPAB, ATF-2/c-Jun, and IRFs. TRAF2 and TRAF6 are two TRAF family proteins that are essential components in TNF-, IL-1- and TLRs-induced NF-?B activation pathways respectively. Our preliminary studies have identified a novel protein designated as NKIP that interacts with TRAF2, TRAF6 and IRF-3. Overexpression of NKIP potently activates NF-kappaB as well as ISRE, an enhancer element found in promoters of type I IFNs and recognized by activated IRF-3. Depletion of NKIP by RNAi significantly inhibits TNF- and IL-1- induced NF-kappaAB activation, and TLRS- and Sendai virus-induced ISRE activation. We hypothesize that NKIP is an essential component of the NF-kappaB and ISRE activation pathways triggered by TNF-, IL-1-, TLRS- and viral infection respectively, and is involved in signaling in inflammation and innate immunity against virus. The goals of this proposal are to determine the mechanisms of NKIP action in signaling by TNF, IL-1, TLR3 and viral infection and its roles in inflammation and innate immunity against virus in vivo.
In Specific Aim #1, various biochemical and molecular biology experiments will be performed to determine the molecular mechanisms of NKIP-mediated NF-kappaB activation pathways.
In Specific Aim #2, experiments will be performed to determine the molecular mechanisms of NKIP-mediated ISRE activation pathways and the roles of NKIP in cellular anti-viral response.
In Specific Aim #3, NKIP gene knockout mice will be produced and used to determine the roles of NKIP in inflammation and innate immunity against viral infection in vivo. Successful completion of these studies will provide important basis for understanding the biochemical and molecular mechanisms of NKIP action in inflammation and innate immunity against viral infection.
|Jin, Lei; Getahun, Andrew; Knowles, Heather M et al. (2013) STING/MPYS mediates host defense against Listeria monocytogenes infection by regulating Ly6C(hi) monocyte migration. J Immunol 190:2835-43|
|Abdul-Sater, Ali A; Tattoli, Ivan; Jin, Lei et al. (2013) Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome. EMBO Rep 14:900-6|
|Xu, Liang-Guo; Jin, Lei; Zhang, Bi-Cheng et al. (2012) VISA is required for B cell expression of TLR7. J Immunol 188:248-58|
|Jin, Lei; Hill, Krista K; Filak, Holly et al. (2011) MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di-AMP and cyclic-di-GMP. J Immunol 187:2595-601|
|Jin, L; Xu, L-G; Yang, I V et al. (2011) Identification and characterization of a loss-of-function human MPYS variant. Genes Immun 12:263-9|
|Jin, Lei; Lenz, Laurel L; Cambier, John C (2010) Cellular reactive oxygen species inhibit MPYS induction of IFN?. PLoS One 5:e15142|
|Xu, Liang-Guo; Wang, Yan-Yi; Han, Ke-Jun et al. (2005) VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19:727-40|
|Huang, Jun; Liu, Ting; Xu, Liang-Guo et al. (2005) SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways. EMBO J 24:4018-28|