Serine residues 286, 288, and 293 within the CIITA: a mechanism for down-regulating CIITA activity through phosphorylation.
CIITA is the primary factor activating the expression of the class II MHC genes necessary for the exogenous pathway of Ag processing and presentation. Strict control of CIITA is necessary to regulate MHC class II gene expression and induction of an immune response. We show in this study that the nuclear localized form of CIITA is a predominantly phosphorylated form of the protein, whereas cytoplasmic CIITA is predominantly unphosphorylated. Novel phosphorylation sites were determined to be located within a region that contains serine residues 286, 288, and 293. Double mutations of these residues increased nuclear CIITA, indicating that these sites are not required for nuclear import. CIITA-bearing mutations of these serine residues significantly increased endogenous MHC class II expression, but did not significantly enhance trans-activation from a MHC class II promoter, indicating that these phosphorylation sites may be important for gene activation from intact chromatin rather than artificial plasmid-based promoters. These data suggest a model for CIITA function in which phosphorylation of these specific sites in CIITA in the nucleus serves to down-regulate CIITA activity.
Greer
Susanna F
SF
Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
Harton
Jonathan A
JA
Linhoff
Michael W
MW
Janczak
Christin A
CA
Ting
Jenny P-Y
JP
Cressman
Drew E
DE
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D015536:Down-Regulation; D005802:Genes, MHC Class II; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012694:Serine; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D015533:Transcriptional Activation
C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D012694:Serine