Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Journal of biological chemistry, 2012-07, Vol.287 (29), p.24294-24303

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Most of the nucleotide-binding domain, leucine-rich repeat (NLR) proteins regulate responses to microbial and damage-associated products. Class II transactivator (CIITA) has a distinct function as the master regulator of class II major histocompatibility complex (MHC-II) transcription. Recently, human NLRC5 was found to regulate MHC-I in cell lines; however, a host of conflicting positive and negative functions has been attributed to this protein. To address the function of NLRC5 in a physiologic setting, we generated an Nlrc5−/− strain that contains a deletion in the exon that encodes the nucleotide-binding domain. We have not detected a role for this protein in cytokine induction by pathogen-associated molecular patterns and viruses. However, Nlrc5−/− cells showed a dramatic decrease of classical (H-2K) and nonclassical (Tla) MHC-I expression by T/B lymphocytes, natural killer (NK) cells, and myeloid-monocytic lineages. As a comparison, CIITA did not affect mouse MHC-I expression. Nlrc5−/− splenocytes and bone marrow-derived macrophages were able to up-regulate MHC-I in response to IFN-γ; however, the absolute levels of MHC-I expression were significantly lower than WT controls. Chromatin immunoprecipitation of IFN-γ-treated cells indicates that Nlrc5 reduced the silencing H3K27me3 histone modification, but did not affect the activating AcH3 modification on a MHC-I promoter. In summary, we conclude that Nlrc5 is important in the regulation of MHC-I expression by reducing H3K27me3 on MHC-I promoter and joins CIITA as an NLR subfamily that controls MHC gene transcription. Background: Multiple functions have been ascribed to NLRC5 including MHC-I transcription and cytokine responses. Results: We generated Nlrc5−/− mice and showed that Nlrc5 increases classical and nonclassical MHC-I and causes removal of the gene-silencing H3K27me3 histone modification on MHC-I promoter. Conclusion: Nlrc5 regulates MHC-I expression. Significance: NLRC5, with CIITA, constitutes an NLR subfamily that regulates MHC.