Cutting Edge: Impaired MHC Class I Expression in Mice Deficient for Nlrc5/Class I Transactivator

Biswas, Amlan; Meißner, Torsten; Kawai, Taro; Kobayashi, Koichi S.

doi:10.4049/jimmunol.1200064

Cited by 93 publications

(149 citation statements)

References 24 publications

(37 reference statements)

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“…Because CITA/NLRC5-mediated MHC class I expression is crucial for optimal activation and cytolytic activity of CD8 + T cells (18,19), we next examined the expression level of perforin (PRF1) or granzyme A (GZMA), which are known to be associated with cytotoxic T-cell activity in cancer tissues (23). Indeed, the cohort of 16 solid cancer etiologies revealed a significant positive correlation between NLRC5 expression and PRF1 or GZMA (Fig.…”

Section: Significancementioning

confidence: 99%

“…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-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).…”

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confidence: 99%

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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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Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

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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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207

221

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“…NLRC5 function was examined in NLRC5-deficient mice, the results of which revealed reduced MHC class I expression in lymphocytes, including T, NK and NKT lymphocytes (9,10). NLRC5 localizes to the nucleus of lymphocytes, where it promotes MHC class I gene expression via stimulation of the H-2D and H-2K gene promoters (11,12 and thymus; in addition, NLRC5 is expressed abundantly in the lungs and intestines (10,11,(13)(14)(15)(16)(17)(18). Staehli et al (10) reported that HeLa cells express NLRC5 when induced by interferon-γ.…”

Section: Introductionmentioning

confidence: 99%

NLRC5 expression in tumors and its role as a negative prognostic indicator in stage III non-small-cell lung cancer patients

Guo

Liu

et al. 2015

Oncology Letters

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Abstract. Major histocompatibility complex (MHC) class I molecules have a crucial role in tumor immune evasion; however, the association of MHC class I molecules with outcomes in cancer patients remains controversial. Nucleotide-binding oligomerization-like receptor family caspase recruitment domain-containing 5 (NLRC5) has been reported to be a MHC class I transactivator. However, the expression and function of NLRC5 in cancer remains to be elucidated. The present study aimed to retrospectively examine NLRC5 expression in human tumor tissues and its association with clinical outcomes of non-small-cell lung cancer (NSCLC) stage III patients. The expression of MHC class I and NLRC5 in NSCLC were detected using immunohistochemistry (IHC). The association between their expression levels was assessed using the Pearson's χ 2 test and their association with survival was assessed using Kaplan-Meier analysis and the log-rank test. In addition, the expression of NLRC5 and MHC class I were examined in 323 cases of seven other types of tumors and their correlations were studied. The results revealed that the expression of NLRC5 was correlated with that of MHC class I in NSCLC patients (P=0.008). MHC class I-positive and nuclear NLRC5-positive NSCLC patients were found to have shorter overall survival (OS) rates (log-rank, P=0.032 and P=0.039, respectively). In addition, in the seven different tumor types, there was a significant correlation between MHC class I and NLRC5 nuclear expression (P<0.001) as well as MHC class I and NLRC5 cytoplasmic expression (P=0.003). In conclusion, NLRC5 was demonstrated to be widely expressed in eight tumor tissues and its expression was correlated with that of MHC class I. Of note, nuclear NLRC5-negative and MHC class I-negative stage III NSCLC patients had improved OS rates compared to those with positive expression. Therefore, NLRC5 and MHC class I may be negative prognostic indicators in NSCLC stage III patients.

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“…However, the exact mechanisms how expression of MHC genes is regulated is still poorly defined. Recently, several groups identified NLRC5 as a novel transcriptional regulator of MHC class I genes (2)(3)(4)(5)(6)(7)(8). Both NLRC5 and CIITA belong to the NLR protein family that makes up important intracellular pathogen recognition receptors, such as NOD1, NOD2, and NLRP3 (9).…”

mentioning

confidence: 99%

The N-Terminal Domain of NLRC5 Confers Transcriptional Activity for MHC Class I and II Gene Expression

Neerincx

Jakobshagen

Utermöhlen

et al. 2014

The Journal of Immunology

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Ag presentation to CD4+ and CD8+ T cells depends on MHC class II and MHC class I molecules, respectively. One important regulatory factor of this process is the transcriptional regulation of MHC gene expression. It is well established that MHC class II transcription relies on the NLR protein CIITA. Recently, another NLR protein, NLRC5, was shown to drive MHC class I expression. The molecular mechanisms of the function of NLRC5 however remain largely elusive. In this study, we present a detailed functional study of the domains of NLRC5 revealing that the N-terminal domain of human NLRC5 has intrinsic transcriptional activity. Domain swapping experiments between NLRC5 and CIITA showed that this domain contributes to MHC class I and MHC class II gene expression with a bias for activation of MHC class I promoters. Delivery of this construct by adeno-associated viral vectors upregulated MHC class I and MHC class II expression in human cells and enhanced lysis of melanoma cells by CD8+ cytotoxic T cells in vitro. Taken together, this work provides novel insight into the function of NLRC5 and CIITA in MHC gene regulation.

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Cutting Edge: Impaired MHC Class I Expression in Mice Deficient for Nlrc5/Class I Transactivator

Cited by 93 publications

References 24 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

NLRC5 expression in tumors and its role as a negative prognostic indicator in stage III non-small-cell lung cancer patients

The N-Terminal Domain of NLRC5 Confers Transcriptional Activity for MHC Class I and II Gene Expression

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