Regulation of Class I Major Histocompatibility Complex (MHC) by Nucleotide-binding Domain, Leucine-rich Repeat-containing (NLR) Proteins

Robbins, Gregory R.; Truax, Agnieszka D.; Davis, Beckley K.; Zhang, Lu; Brickey, W. June; Ting, Jenny P.‐Y.

doi:10.1074/jbc.m112.364604

Cited by 65 publications

(85 citation statements)

References 39 publications

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“…A striking feature of CITA/NLRC5 is that it does not solely induce MHC class I genes but also activates other critical genes involved in the MHC class I antigen-presentation pathway, including the immunoproteasome component LMP2 (PSMB9), peptide transporter TAP1, and B2M (14,17), thus regulating most of the key components in the MHC class I antigen-presentation machinery. Nlrc5-deficient mice exhibit impaired constitutive and inducible expression of MHC class I genes in vivo (18)(19)(20)(21)(22). In addition, Nlrc5-deficient cells display an impaired ability to elicit CD8 + T-cell activation, as evidenced by impaired IFN-γ production and diminished cytolytic activity (18,19,21).…”

mentioning

confidence: 99%

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

Yoshihama

Roszik

Downs

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

226

242

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Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and β2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8 + cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers.MHC class I | CITA | cancer | immune evasion | NLRC5

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mentioning

confidence: 99%

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

Yoshihama

Roszik

Downs

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

226

242

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“…As discussed above, NLRC5 is induced by PAMPs (LPS, poly(I:C) and poly(dA:dT)) and IFN-γ which all can increase MHC class I gene expression. We and others found that these PAMPs and IFN-γ induced expression of MHC class I genes was also reduced upon NLRC5 deficiency (Biswas et al, 2012;Robbins et al, 2012;Staehli et al, 2012;Yao et al, 2012). Thus, NLRC5 specifically regulates both constitutive and inducible expression of MHC class I genes.…”

Section: Roles Of Nlrc5 In Regulating Immune Responses Nlrc5 Is a Masmentioning

confidence: 82%

“…All these data suggest that NLRC5 regulates the expression of MHC class I genes in different cell types. In contrast, the MHC class II gene expression was not affected in Nlrc5-defi cient mice (Robbins et al, 2012), confi rming that NLRC5 specifically regulates MHC class I genes. As discussed above, NLRC5 is induced by PAMPs (LPS, poly(I:C) and poly(dA:dT)) and IFN-γ which all can increase MHC class I gene expression.…”

Section: Roles Of Nlrc5 In Regulating Immune Responses Nlrc5 Is a Masmentioning

confidence: 85%

“…The negative roles of NLRC5 appear to be cell type specific because IL-6 and IFN-β level were detected higher in Nlrc5-defi cient mouse embryonic fi broblasts (MEFs), peritoneal macrophages and bone marrow-derived macrophages, but not in NLRC5 defi cient BMDCs after TLR stimulation or VSV infection (Tong et al, 2012). However, the inhibitory roles of NLRC5 in type I IFN production and NF-κB were not observed in the other NLRC5 deficient mice in which exon 4, exon 3-4 or exon 1-4 was selected to be targeted by several groups (Kumar et al, 2010;Robbins et al, 2012;Staehli et al, 2012;Yao et al, 2012). The discrepancy is likely due to the differential targeting strategies.…”

Section: Function Of Nlrc5 In Innate Immune Responsementioning

confidence: 99%

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Expression regulation and function of NLRC5

Yao

Qian

2013

Protein Cell

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The NOD like receptors (NLRs), a class of intracellular receptors that respond to pathogen attack or cellular stress, have gained increasing attention. NLRC5, the largest member of the NLR protein family, has recently been identified as a critical regulator of immune responses. While NLRC5 is constitutively and widely expressed, it can be dramatically induced by interferons during pathogen infections. Both in vitro and in vivo studies have demonstrated that NLRC5 is a specifi c and master regulator of major mistocompatibility complex (MHC) class I genes as well as related genes involved in MHC class I antigen presentation. The expression of MHC class I genes is regulated by NLRC5 in coordination with the RFX components through an enhanceosome-dependent manner. And the involvement of NLRC5 in MHC class I mediated CD8 + T cell activation, proliferation and cytotoxicity is proved to be critical for host defense against intracellular bacterial infections. Nevertheless, the role of NLRC5 in innate immunity remains to be further explored. Here, we review the research advances on the structure, expression regulation and function of NLRC5.

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“…The numbers of CD8 ϩ T cells are only mildly reduced in spleen, lymph node, and liver of NLRC5Ϫ/Ϫ mice (21,240,264,291), in contrast to severely reduced number of CD8 ϩ T cells in mice lacking MHC class I expression due to mutations in the ␤2-m gene (301). However, the lack of NLRC5 impairs the ability to induce antigen-specific CD8…”

Section: Nlrc5 and Ciitamentioning

confidence: 92%

NOD-Like Receptors: Versatile Cytosolic Sentinels

Motta

Soares

Sun

et al. 2015

Physiological Reviews

275

206

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Nucleotide binding oligomerization domain (NOD)-like receptors are cytoplasmic pattern-recognition receptors that together with RIG-I-like receptor (retinoic acid-inducible gene 1), Toll-like receptor (TLR), and C-type lectin families make up the innate pathogen pattern recognition system. There are 22 members of NLRs in humans, 34 in mice, and even a larger number in some invertebrates like sea urchins, which contain more than 200 receptors. Although initially described to respond to intracellular pathogens, NLRs have been shown to play important roles in distinct biological processes ranging from regulation of antigen presentation, sensing metabolic changes in the cell, modulation of inflammation, embryo development, cell death, and differentiation of the adaptive immune response. The diversity among NLR receptors is derived from ligand specificity conferred by the leucine-rich repeats and an NH2-terminal effector domain that triggers the activation of different biological pathways. Here, we describe NLR genes associated with different biological processes and the molecular mechanisms underlying their function. Furthermore, we discuss mutations in NLR genes that have been associated with human diseases.

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Regulation of Class I Major Histocompatibility Complex (MHC) by Nucleotide-binding Domain, Leucine-rich Repeat-containing (NLR) Proteins

Abstract: Background: Multiple functions have been ascribed to NLRC5 including MHC-I transcription and cytokine responses. Results: We generated Nlrc5 Ϫ/Ϫ mice and showed that Nlrc5 increases classical and nonclassical MHC-I and causes removal of

Cited by 65 publications

References 39 publications

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

NLRC5/MHC class I transactivator is a target for immune evasion in cancer

Expression regulation and function of NLRC5

NOD-Like Receptors: Versatile Cytosolic Sentinels

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