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J. Biol. Chem., Vol. 283, Issue 3, 1243-1256, January 18, 2008

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CIITA Mediates Interferon- Repression of Collagen Transcription through Phosphorylation-dependent Interactions with Co-repressor Molecules^*

Yong Xu, Jonathan A. Harton, and Barbara D. Smith¹

From the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118 and Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208

Previously, we have demonstrated that major histocompatibility class II trans-activator (CIITA) is crucial in mediating interferon- (IFN-)-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--mediated recruitment of Sin3B and HDAC2 to the collagen start site. Therefore, we have identified the region within CIITA responsible for mediating IFN--induced inhibition of collagen synthesis.

Received for publication, August 27, 2007 , and in revised form, November 6, 2007.

^* This work was supported by National Institutes of Health Public Health Services Grants HL68094 and HL013262-31 (to B. D. S.) and by American Heart Association Post-doctoral Fellowship Grant 0525981T (to Y. X.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4159; Fax: 617-638-5339; E-mail: smith{at}biochem.bumc.bu.edu.

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