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-γ–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-γ–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 β2-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.
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CIITA expression is restricted to antigen-presenting cells.
“While CIITA expression is restricted to antigen-presenting cells, NLRC5 is constitutively expressed in various tissues, most highly in cells from the hematopoietic lineage (CD4 + T cells, CD8 + T cells, CD19 + B cells, natural killer cells and natural killer T cells).”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [39]
NLRC5 is constitutively expressed in various tissues, most highly in cells from the hematopoietic lineage (CD4+ T cells, CD8+ T cells, CD19+ B cells, natural killer cells and natural killer T cells).
“While CIITA expression is restricted to antigen-presenting cells, NLRC5 is constitutively expressed in various tissues, most highly in cells from the hematopoietic lineage (CD4 + T cells, CD8 + T cells, CD19 + B cells, natural killer cells and natural killer T cells).”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [39]
NLRC5 and CIITA are the respective master regulators of MHC class I and II gene expression.
“NLRC5 and CIITA are the respective master regulators of MHC class I and II gene expression 39 .”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [39]
NLRC5 expression levels are intermediate in monocytic CD14+ cells and CD11B+ splenic myeloid cells.
“NLRC5 expression levels are intermediate in monocytic CD14 + cells and CD11B + splenic myeloid cells.”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [39]
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Cites
Regulation of MHC Class II Expression by Interferon-γ Mediated by the Transactivator Gene CIITA
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Self-citationNLRs at the intersection of cell death and immunity
Ting, J. P.-Y., Willingham, S. B., & Bergstralh, D. T. (2008) · Nature Reviews Immunology · doi:10.1038/nri2296 · Cited by 371 · cited 4× · see citing works
“There are 22 NLR proteins in humans, which share three characteristic functional domains: an N-terminal protein–protein interaction domain such as a caspase recruitment domain (CARD) or a PYRIN domain, a centrally located NBD (or NACHT, NAIP, CIITA, HET-E and TP1 domain), and C-terminal LRRs (11, 12).”
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- Authors
- Meissner, T. B., Li, A., Biswas, A., Lee, K.-H., Liu, Y.-J., Bayir, E., Iliopoulos, D., van den Elsen, P. J., & Kobayashi, K. S.
- Affiliations
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115;
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-07-16
- Volume
- 107
- Issue
- 31
- Pages
- 13794-13799
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 408
- References
- 3
- Language
- en
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