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NLR family member NLRC5 is a transcriptional regulator of MHC class I genes.

ABSTRACT: MHC class I plays a critical role in the immune defense against viruses and tumors by presenting antigens to CD8 T cells. An NLR protein, class II transactivator (CIITA), is a key regulator of MHC class II gene expression that associates and cooperates with transcription factors in the MHC class II promoter. Although CIITA also transactivates MHC class I gene promoters, loss of CIITA in humans and mice results in the severe reduction of only MHC class II expression, suggesting that additional mechanisms regulate the expression of MHC class I. Here, we identify another member of the NLR protein family, NLRC5, as a transcriptional regulator of MHC class I genes. Similar to CIITA, NLRC5 is an IFN-gamma-inducible nuclear protein, and the expression of NLRC5 resulted in enhanced MHC class I expression in lymphoid as well as epithelial cell lines. Using chromatin immunoprecipitation and reporter gene assays, we show that NLRC5 associates with and activates the promoters of MHC class I genes. Furthermore, we show that the IFN-gamma-induced up-regulation of MHC class I requires NLRC5, because knockdown of NLRC5 specifically impaired the expression of MHC class I. In addition to MHC class I genes, NLRC5 also induced the expression of beta2-microglobulin, transporter associated with antigen processing, and large multifunctional protease, which are essential for MHC class I antigen presentation. Our results suggest that NLRC5 is a transcriptional regulator, orchestrating the concerted expression of critical components in the MHC class I pathway.

SUBMITTER: Meissner TB

PROVIDER: S-EPMC2922274 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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NLR family member NLRC5 is a transcriptional regulator of MHC class I genes.

Meissner Torsten B TB Li Amy A Biswas Amlan A Lee Kyoung-Hee KH Liu Yuen-Joyce YJ Bayir Erkan E Iliopoulos Dimitrios D van den Elsen Peter J PJ Kobayashi Koichi S KS

Proceedings of the National Academy of Sciences of the United States of America 20100716 31

MHC class I plays a critical role in the immune defense against viruses and tumors by presenting antigens to CD8 T cells. An NLR protein, class II transactivator (CIITA), is a key regulator of MHC class II gene expression that associates and cooperates with transcription factors in the MHC class II promoter. Although CIITA also transactivates MHC class I gene promoters, loss of CIITA in humans and mice results in the severe reduction of only MHC class II expression, suggesting that additional me ...[more]

PMID: 20639463

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Project description:MHC class II (MHCII) genes are transactivated by the NOD-like receptor (NLR) family member CIITA, which is recruited to SXY enhancers of MHCII promoters via a DNA-binding "enhanceosome" complex. NLRC5, another NLR protein, was recently found to control transcription of MHC class I (MHCI) genes. However, detailed understanding of NLRC5's target gene specificity and mechanism of action remained lacking. We performed ChIP-sequencing experiments to gain comprehensive information on NLRC5-regulated genes. In addition to classical MHCI genes, we exclusively identified novel targets encoding non-classical MHCI molecules having important functions in immunity and tolerance. ChIP-sequencing performed with Rfx5(-/-) cells, which lack the pivotal enhanceosome factor RFX5, demonstrated its strict requirement for NLRC5 recruitment. Accordingly, Rfx5-knockout mice phenocopy Nlrc5 deficiency with respect to defective MHCI expression. Analysis of B cell lines lacking RFX5, RFXAP, or RFXANK further corroborated the importance of the enhanceosome for MHCI expression. Although recruited by common DNA-binding factors, CIITA and NLRC5 exhibit non-redundant functions, shown here using double-deficient Nlrc5(-/-)CIIta(-/-) mice. These paradoxical findings were resolved by using a "de novo" motif-discovery approach showing that the SXY consensus sequence occupied by NLRC5 in vivo diverges significantly from that occupied by CIITA. These sequence differences were sufficient to determine preferential occupation and transactivation by NLRC5 or CIITA, respectively, and the S box was found to be the essential feature conferring NLRC5 specificity. These results broaden our knowledge on the transcriptional activities of NLRC5 and CIITA, revealing their dependence on shared enhanceosome factors but their recruitment to distinct enhancer motifs in vivo. Furthermore, we demonstrated selectivity of NLRC5 for genes encoding MHCI or related proteins, rendering it an attractive target for therapeutic intervention. NLRC5 and CIITA thus emerge as paradigms for a novel class of transcriptional regulators dedicated for transactivating extremely few, phylogenetically related genes.

Project description:Major histocompatibility complex class I (MHC-I) and MHC-II molecules, mainly being responsible for the processing and presentation of intracellular or extracellular antigen, respectively, are critical for antiviral immunity. Here, we reported that porcine deltacoronavirus (PDCoV) with the zoonotic potential and potential spillover from pigs to humans, upregulated the expressions of porcine MHC-I (swine leukocyte antigen class I, SLA-I) molecules and SLA-I antigen presentation associated genes instead of porcine MHC-II (SLA-II) molecules both in primary porcine enteroids and swine testicular (ST) cells at the late stage of infection, and this finding was verified in vivo. Moreover, the induction of SLA-I molecules by PDCoV infection was mediated through enhancing the expression of NOD-like receptor (NLR) family caspase recruitment domain-containing 5 (NLRC5). Mechanistic studies demonstrated that PDCoV infection robustly elevated retinoic acid-inducible gene I (RIG-I) expression, and further initiated the downstream type I interferon beta (IFN-β) production, which led to the upregulation of NLRC5 and SLA-I genes. Likewise, interferon regulatory factor 1 (IRF1) elicited by PDCoV infection directly activated the promoter activity of NLRC5, resulting in an increased expression of NLRC5 and SLA-I upregulation. Taken together, our findings advance our understanding of how PDCoV manipulates MHC molecules, and knowledge that could help inform the development of therapies and vaccines against PDCoV. IMPORTANCE MHC-I molecules play a crucial role in antiviral immunity by presenting intracellular antigens to CD8+T lymphocytes and eliminating virus-infected cells by natural killer cells' "missing-self recognition." However, the manipulation of MHC molecules by coronaviruses remains poorly understood. Here, we demonstrated that PDCoV, a zoonotic potential coronavirus efficiently infecting cells from broad species, greatly increased the expressions of porcine MHC-I (SLA-I) molecules and MHC-I antigen presentation associated genes but not porcine MHC-II (SLA-II) molecules both in vitro and in vivo. Mechanistically, the upregulation of MHC-I molecules by PDCoV infection required the master transactivator of MHC-I, NLRC5, which was mediated not only by RIG-I-initiated type I IFN signaling pathway but also by IRF1 induced by PDCoV as it could activate NLRC5 promoter activity. These results provide significant insights into the modification of the MHC class I pathway and may provide a potential therapeutic intervention for PDCoV.

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NLR family member NLRC5 is a transcriptional regulator of MHC class I genes.

Publications

NLR family member NLRC5 is a transcriptional regulator of MHC class I genes.

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