The nucleotide-binding domain of NLRC5 is critical for nuclear import and transactivation activity.
Major histocompatibility complex (MHC) class I and class II are crucial for the function of the human adaptive immune system. A member of the NLR (nucleotide-binding domain, leucine-rich repeat) protein family, NLRC5, has recently been identified as a transcriptional regulator of MHC class I and related genes. While a 'master regulator' of MHC class II genes, CIITA, has long been known, NLRC5 specifically associates with and transactivates the proximal promoters of MHC class I genes. In this study, we analyzed the molecular requirements of NLRC5 nuclear import and transactivation activity. We show that NLRC5-mediated MHC class I gene induction requires an intact nuclear localization signal and nuclear distribution of NLRC5. In addition, we find that the nucleotide-binding domain (NBD) of NLRC5 is critical not only for nuclear translocation but also for the transactivation of MHC class I genes. Changing the cellular localization of NLRC5 is likely to immediately impact MHC class I expression as well as MHC class I-mediated antigen presentation. NLRC5 may thus provide a promising target for the modulation of MHC class I antigen presentation, especially in the setting of transplant medicine.
Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, MA 02215, United States.
Torsten B
TB
Meissner
Amy
A
Li
Yuen-Joyce
YJ
Liu
Etienne
E
Gagnon
Koichi S
KS
Kobayashi
D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism*; D005805:Genes, MHC Class I; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism*; D009711:Nucleotides / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation
D047908:Intracellular Signaling Peptides and Proteins; C548042:NLRC5 protein, human; D019913:Nuclear Localization Signals; D009711:Nucleotides