NLRC5 Cooperates with the RFX Transcription Factor Complex To Induce MHC Class I Gene Expression

Meißner, Torsten; Liu, Yuen-Joyce; Lee, Kyoung-Hee; Li, Amy; Biswas, Amlan; Eggermond, Marja C.J.A. van; Elsen, Peter J. van den; Kobayashi, Koichi S.

doi:10.4049/jimmunol.1103160

Cited by 102 publications

(120 citation statements)

References 53 publications

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“…On the other hand, the HTNV N protein has been demonstrated to interfere with NF-κB activation [38]. Thus, hantavirus-triggered PRRs may facilitate the assembly of a MHC-I-specific enhanceosome that binds to promoter sequences different from the NF-κB binding site as shown for NLRC5 [39,40]. Compared to DCs stimulated with TNF-α, HTNV-infected DCs show increased macropinocytosis and receptor-mediated endocytosis [23], a prerequisite of cross-presentation.…”

Section: Discussionmentioning

confidence: 99%

Hantaviral mechanisms driving HLA class I antigen presentation require both RIG‐I and TRIF

et al. 2013

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Hantaviruses are emerging human pathogens. They induce an unusually strong antiviral response of human HLA class I (HLA-I) restricted CD8 + T cells that may contribute to tissue damage and hantavirus-associated disease. In this study, we analyzed possible hantaviral mechanisms that enhance the HLA-I antigen presentation machinery. Upon hantavirus infection of various human and primate cell lines, we observed transactivation of promoters controlling classical HLA molecules. Hantavirus-induced HLA-I upregulation required proteasomal activity and was associated with increased TAP expression. Intriguingly, human DCs acquired the capacity to cross-present antigen upon hantavirus infection. Furthermore, knockdown of TIR domain containing adaptor inducing IFN-β or retinoic acid inducible gene I abolished hantavirus-driven HLA-I induction. In contrast, MyD88-dependent viral sensors were not involved in HLA-I induction. Our results show that hantaviruses strongly boost the HLA-I antigen presentation machinery by mechanisms that are dependent on both retinoic acid inducible gene I and TIR domain containing adaptor inducing IFN-β.Keywords: Antigen presentation/processing · Cross-presentation/priming · Immunopathology · Infectious diseases · Innate immunity IntroductionRapidly changing ecosystems and climate facilitate the emergence of human infections with hantaviruses [1][2][3]. In Germany, increasing numbers of hantavirus-associated disease cases have been observed [4]. The enhanced health hazard emanating from pathogenic hantavirus species has been recognized by the German National Health Institute, which has recently reprioritized infecCorrespondence: Prof. Günther Schönrich e-mail: guenther.schoenrich@charite.de tious pathogens and placed hantaviruses in the highest priority group [5].Hantaviruses belong to the family Bunyaviridae and have segmented genomes [6]. The three viral RNA segments code for a nucleoprotein (N), two glycoproteins (Gn and Gc), and a RNA-dependent RNA polymerase. Hantaviruses are transmitted to humans by inhalation of virus-containing aerosols that are derived from the excreta of hantavirus-infected rodents. These natural reservoir hosts remain asymptomatic, although they are persistently infected. In striking contrast, hantaviruses are eliminated in humans at the cost of severe symptoms such as pulmonary or renal failure. Currently, no suitable vaccines or therapeutics are C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2566-2576 Antigen processing 2567 available for prevention or treatment of human hantavirus infections [7,8].Hantaviruses are not directly cytopathic for infected cells, suggesting that the antiviral immune response itself causes hantavirus-associated syndromes [9,10]. In accordance, hantaviruses trigger an unusually potent reaction of CD8 + T lymphocytes, that is devoid of regulatory T cells, and still detectable years after resolution [11][12][13][14]. Human CD8 + T cells are stimulated by HLA class I (HLA-I) molecules that prese...

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Section: Discussionmentioning

confidence: 99%

Hantaviral mechanisms driving HLA class I antigen presentation require both RIG‐I and TRIF

et al. 2013

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“…Transcriptional regulation of MHC class I genes remained largely undefined until the recent discovery of CITA (MHC class I transactivator), known as NLRC5 [NODlike receptor (NLR) family, caspase recruitment (CARD) domain containing 5] (11,12). NLRC5 is an IFN-γ-inducible nuclear protein (13)(14)(15) that specifically associates with and activates promoters of MHC class I genes by generating a CITA enhanceosome complex with other transcription factors (14,16,17). 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.…”

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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.

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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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“…Subsequent experiments collectively establish a critical role of NLRC5 in regulating MHC class I-mediated antigen-specific CD8 + T cell activation, proliferation as well as cytotoxicity, highlighting the importance of NLRC5 in host defense against bacterial infection. The function of NLRC5 in regulating MHC class I are further substantiated by three other competing studies [4][5][6], one of which shows that NLCR5 interacts with the RFX transcription factor complex to transactivate the promoters of MHC class I genes [4].…”

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confidence: 85%