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.
|Huang, Juin-Hua; Liu, Chu-Yu; Wu, Sheng-Yang et al. (2018) NLRX1 Facilitates Histoplasma capsulatum-Induced LC3-Associated Phagocytosis for Cytokine Production in Macrophages. Front Immunol 9:2761|
|Swanson, Karen V; Junkins, Robert D; Kurkjian, Cathryn J et al. (2017) A noncanonical function of cGAMP in inflammasome priming and activation. J Exp Med 214:3611-3626|
|Freeman, Leslie; Guo, Haitao; David, Clément N et al. (2017) NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J Exp Med 214:1351-1370|
|Zhang, Song; Takaku, Motoki; Zou, Liyun et al. (2017) Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation. Nature 551:105-109|
|Rotty, Jeremy D; Brighton, Hailey E; Craig, Stephanie L et al. (2017) Arp2/3 Complex Is Required for Macrophage Integrin Functions but Is Dispensable for FcR Phagocytosis and In Vivo Motility. Dev Cell 42:498-513.e6|
|Bruce, Danny W; Stefanski, Heather E; Vincent, Benjamin G et al. (2017) Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease. J Clin Invest 127:1813-1825|
|Chen, Liang; Wilson, Justin E; Koenigsknecht, Mark J et al. (2017) NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nat Immunol 18:541-551|
|Snouwaert, John N; Nguyen, MyTrang; Repenning, Peter W et al. (2016) An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice. Cell Rep 17:3077-3088|
|Guo, Haitao; König, Renate; Deng, Meng et al. (2016) NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses. Cell Host Microbe 19:515-528|
|Koblansky, A Alicia; Truax, Agnieszka D; Liu, Rongrong et al. (2016) The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals. Cell Rep 14:2562-75|
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