CIITA mediates interferon-gamma repression of collagen transcription through phosphorylation-dependent interactions with co-repressor molecules.
Previously, we have demonstrated that major histocompatibility class II trans-activator (CIITA) is crucial in mediating interferon-gamma (IFN-gamma)-induced repression of collagen type I gene transcription. Here we report that CIITA represses collagen transcription through a phosphorylation-dependent interaction between its proline/serine/threonine domain and co-repressor molecules such as histone deacetylase (HDAC2) and Sin3B. Mutation of a serine (S373A) in CIITA, within a glycogen synthase kinase 3 (GSK3) consensus site, decreases repression of collagen transcription by blocking interaction with Sin3B. In vitro phosphorylation of CIITA by GSK3 relies on a casein kinase I site three amino acids C-terminal to the GSK3 site in CIITA. Both GSK3 and casein kinase I inhibitors alleviate collagen repression and disrupt IFN-gamma-mediated recruitment of Sin3B and HDAC2 to the collagen start site. Therefore, we have identified the region within CIITA responsible for mediating IFN-gamma-induced inhibition of collagen synthesis.
Xu
Yong
Y
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118.
Harton
Jonathan A
JA
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208.
Smith
Barbara D
BD
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118. Electronic address: smith@biochem.bumc.bu.edu.
D000595:Amino Acid Sequence; D000818:Animals; D047389:Casein Kinase I / Q000037:antagonists & inhibitors; D002460:Cell Line; D003094:Collagen / Q000235:genetics*; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry; D000949:Histocompatibility Antigens Class II; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004791:Enzyme Inhibitors; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D050505:Mutant Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C492042:SIN3B protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D012694:Serine; D007371:Interferon-gamma; D003094:Collagen; D047389:Casein Kinase I; D038362:Glycogen Synthase Kinase 3