The Nucleotide-binding domain, leucine-rich repeat family is comprised of 22 genes. Among this family, the CIITA (class II transactivator) is the founding member. CIITA is the master transcriptional activator regulator of both classical and nonclassical (DM and DOa) MHC-ll genes. In addition to MHC-II, we identified Plexin Al (Plxnal) as a novel gene that is also regulated by CIITA in dendritic cells. The Plexin molecules comprise a large gene family and are considered the receptor for semaphorin family members. They were initially identified in neurons as important for neuronal guidance and axonal growth and serve as either retractive or attractive signals to guide axonal extension. During the last three and a half years, a large component of our effort was focused on the initial aims which are largely accomplished as follows: (1) We found that the Plxnal gene has two promoters, one of which is regulated by CIITA, other transcription factors and by histone modifying enzymes;by contrast, a promoter that is more preferentially utilized in neuronal cells is not regulated by CIITA;(2) we showed that Plexin A l affects the Rho GTPase pathway to alter actin polarization in dendritic cells;and (3) we showed that Sema6p on T cells and PIxnAI on DC represent a pair of ligand-receptor, and the T cell signaling pathway that is activated upon Sema6D engagement is conducted via the c-abl/CrL pathway. In addition to what we proposed, we significantly expanded the scope to identify other immune plexin family members and their functional and molecular role in the immune system. We identified and revealed three plexins and their immune functions: (1) Plexin-A4 is a surface molecule expressed by macrophages and dendritic cells that is required for optimal signaling through TLR to cause Rac GTPase activation;(2) Plexin-B2 is expressed by macrophages and is important for cell motility by regulating Rac and Cdc42 activation;and (3) Plexin-DI is expressed by lymphocytes and regulates germinal B cell migration and development. In addition, we also expanded our analysis to the transcriptional regulation of NLRs, including CIITA and NLRP12 and found that both are inhibited by the Blimp-1 factor. In the new proposal, we plan to examine the role of plexins in inflammatory disorders, and to study the regulation of NLR gene transcription.
The Nucleotide-binding domain, leucine-rich repeat containing family (NLR) has gained much attention due to their effects on adaptive and innate immunity. One ofthe founding members, CIITA, induces the transcription of Plexin-AI. This work will focus on the disease-relevance of plexins, on the transcriptional regulation of NLRs, and on the interactome that contains NLR to influence gene transcription that can affect immunologic outcome and diseases.
|Rodgers, Mary A; Bowman, James W; Fujita, Hiroaki et al. (2014) The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med 211:1333-47|
|Robbins, Gregory R; Wen, Haitao; Ting, Jenny P-Y (2014) Inflammasomes and metabolic disorders: old genes in modern diseases. Mol Cell 54:297-308|
|Zhang, Lu; Mo, Jinyao; Swanson, Karen V et al. (2014) NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. Immunity 40:329-41|
|Guo, Haitao; Gao, Jianmei; Taxman, Debra J et al. (2014) HIV-1 infection induces interleukin-1? production via TLR8 protein-dependent and NLRP3 inflammasome mechanisms in human monocytes. J Biol Chem 289:21716-26|
|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|
|Wen, Haitao; Miao, Edward A; Ting, Jenny P-Y (2013) Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39:432-41|
|Wen, Haitao; Ting, Jenny P-Y; O'Neill, Luke A J (2012) A role for the NLRP3 inflammasome in metabolic diseases--did Warburg miss inflammation? Nat Immunol 13:352-7|
|Wen, Haitao; Gris, Denis; Lei, Yu et al. (2011) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12:408-15|
|Smith, Matthew A; Wright, Gabriela; Wu, Jian et al. (2011) Positive regulatory domain I (PRDM1) and IRF8/PU.1 counter-regulate MHC class II transactivator (CIITA) expression during dendritic cell maturation. J Biol Chem 286:7893-904|
|Roney, Kelly E; O'Connor, Brian P; Wen, Haitao et al. (2011) Plexin-B2 negatively regulates macrophage motility, Rac, and Cdc42 activation. PLoS One 6:e24795|
Showing the most recent 10 out of 12 publications