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NLRC5: a key regulator of MHC class I-dependent immune responses

Nature Reviews Immunology volume 12, pages 813–820 (2012)Cite this article

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Abstract

The expression of MHC class I molecules is crucial for the initiation and regulation of adaptive immune responses against pathogens. NOD-, LRR- and CARD-containing 5 (NLRC5) was recently identified as a specific transactivator of MHC class I genes (CITA). NLRC5 and the master regulator for MHC class II genes, class II transactivator (CIITA), interact with similar MHC promoter-bound factors. Here, we provide a broad overview of the molecular mechanisms behind MHC class I transcription and the role of the class I transactivator NLRC5 in MHC class I-dependent immune responses.

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Figure 1: The MHC class I and MHC class II antigen-presentation pathways.
Figure 2: Cis-regulatory elements in the proximal promoters of MHC class I and MHC class II genes.
Figure 3: MHC class I and MHC class II gene transactivation.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health and the Broad Medical Research Program of the Eli and Edythe L. Broad Foundation (to K.S.K.). K.S.K. is a recipient of the Investigator Award from the Cancer Research Institute and the Claudia Adams Barr Award for Innovative Basic Cancer Research. The work of P.v.d.E. was supported by grants from the Dutch Cancer Society, the Dutch MS Research Foundation and the Netherlands Organization for Research. The authors thank Y.-J. Liu for proofreading the manuscript.

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Authors and Affiliations

  1. Koichi S. Kobayashi is at the Department of Microbial and Molecular Pathogenesis, College of Medicine, Texas A&M Health Science Center, 415A Reynolds Medical Building, College Station, Texas 77843, USA.,

    Koichi S. Kobayashi

  2. Koichi S. Kobayashi is also at the Department of Cancer Immunology and AIDS, and the Department of Microbiology and Immunobiology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.,

    Koichi S. Kobayashi

  3. Peter J. van den Elsen is at the Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Building 1, E3-Q, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.,

    Peter J. van den Elsen

  4. Peter J. van den Elsen is also at the Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.,

    Peter J. van den Elsen

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Correspondence to Koichi S. Kobayashi or Peter J. van den Elsen.

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Glossary

BRG1

The ATPase BRG1 is the catalytic subunit of the human SWI/SNF complex that is needed for nucleosome remodelling to provide a more open chromatin structure. This open structure facilitates the interaction of transcription factors with their cognate binding sites in gene regulatory elements to promote transcription.

Enhanceosome

A multiprotein complex containing transcription factors, co-activators and additional proteins that binds to regulatory regions in genes (such as proximal promoters and/or enhancers) to accelerate gene transcription.

Histone acetyltransferases

Enzymes that mediate the addition of an acetyl group to lysine residues that are located at the N-termini of histones. Histone acetylation facilitates transcription.

Histone deacetylases

Enzymes that remove the acetyl groups from lysine residues that are located at the N-termini of histones. In general, decreased levels of histone acetylation are associated with the repression of gene expression. The balance of histone acetylation is maintained by the interplay between histone deacetylases and histone acetyltransferases.

Histone demethylases

Enzymes that remove the methyl groups from modified lysine residues in histones.

Histone methyltransferases

Enzymes that catalyse the transfer of methyl groups to lysine and/or arginine residues in histones. Depending on the residue that is methylated, this histone modification is associated with either gene repression or gene activation.

Inflammasome

A large multiprotein complex composed of an NLR protein, the adaptor protein ASC and caspase 1. Inflammasomes contribute to the secretion of IL-1β and IL-18 by activating caspase 1.

MHC class II deficiency

(Also known as bare lymphocyte syndrome (BLS)). A severe combined immune deficiency disease recognized by the lack of MHC class II molecule expression owing to defects in CIITA (type II BLS) or in RFX components (namely RFXBANK, RFXAP or RFX5; type III BLS).

NOD-like receptor

(NLR; also known as a nucleotide-binding domain, leucine-rich repeat-containing protein). A member of a diverse family of cytosolic pattern-recognition molecules that are involved in the innate immune sensing of pathogens and inflammatory responses.

Nucleotide-binding domain

(NBD; also known as a nucleotide-binding oligomerization domain). A domain that is crucial for the function of NLR proteins. The NBD induces the oligomerization or dimerization of proteins following the binding and hydrolysis of ATP or GTP.

Retinoic acid-inducible gene I signalling

(RIG-I signalling). A signalling pathway that is activated by the interaction of viral RNA with the receptor RIG-I. Through the adaptor protein MAVS (also known as IPS1, VISA and CARDIF), these signals activate the transcription factors IRF3 and IRF7, leading to the production of type I interferons.

Regulatory factor X complex

(RFX complex). RFX drives the assembly of the multiprotein complex on the SXY module of MHC gene promoters. RFX components fail to assemble this complex if genetic defects of RFX genes exist, and this results in rare hereditary immunodeficiency diseases (type III bare lymphocyte syndrome), characterized by the absence of MHC class II expression associated with reduced levels of MHC class I expression.

SUG1

The ATPase SUG1 is a component of the regulatory 19S proteasome cap complex and appears to be important for regulating histone H3 acetylation at MHC proximal promoters. Furthermore, SUG1 is also required for recruiting CBP and CIITA to MHC proximal promoters.

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Kobayashi, K., van den Elsen, P. NLRC5: a key regulator of MHC class I-dependent immune responses. Nat Rev Immunol 12, 813–820 (2012). https://doi.org/10.1038/nri3339

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