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J. Biol. Chem., Vol. 279, Issue 39, 40529-40535, September 24, 2004

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The S Box of Major Histocompatibility Complex Class II Promoters Is a Key Determinant for Recruitment of the Transcriptional Co-activator CIITA^*

Annick Muhlethaler-Mottet, Michal Krawczyk, Krzysztof Masternak¶, Charalambos Spilianakis||**, Androniki Kretsovali||, Joseph Papamatheakis||, and Walter Reith

From the University of Geneva Medical School, Department of Pathology and Immunology, Centre Médical Universitaire, 1 rue Michel-Servet, CH-1211, Geneva, Switzerland and the ^||Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology, Vasilika Vouton, Heraklion 71110, Crete

Tightly regulated expression of major histocompatibility complex (MHC) class II genes is critical for the immune system. A conserved regulatory module consisting of four cis-acting elements, the W, X, X2 and Y boxes, controls transcription of MHC class II genes. The X, X2, and Y boxes are bound, respectively, by RFX, CREB, and NF-Y to form a MHC class II-specific enhanceosome complex. The latter constitutes a landing pad for recruitment of the transcriptional co-activator CIITA. In contrast to the well defined roles of the X, X2, and Y boxes, the role of the W region has remained controversial. In vitro binding studies have suggested that it might contain a second RFX-binding site. We demonstrate here by means of promoter pull-down assays that the most conserved subsequence within the W region, called the S box, is a critical determinant for tethering of CIITA to the enhanceosome complex. Binding of CIITA to the enhanceosome requires both integrity of the S box and a remarkably stringent spacing between the S and X boxes. Even a 1–2-base pair change in the native S-X distance is detrimental for CIITA recruitment and promoter function. In contrast to current models, binding of RFX to a putative duplicated binding site in the W box is thus not required for either CIITA recruitment or promoter activity. This paves the way for the identification of novel factors mediating the contribution of the S box to the activation of MHC class II promoters.

Received for publication, June 14, 2004 , and in revised form, July 14, 2004.

^* This work was supported by the Swiss National Science Foundation, by the Swiss Commission pour la Technologie et de l'Innovation, and by a contribution from NovImmune S.A. 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.

Supported by the Marie Heim-Vögtlin Foundation. Present address: Onco-hematology Research Unit, Pediatrics, University Hospital of Vaud, CHUV, CH-1011, Lausanne, Switzerland.

^¶ Present address: NovImmune S.A., 64 avenue de la Roseraie, CH-1211, Geneva, Switzerland.

^** Present address: Section of Immunobiology, Yale School of Medicine, 300 Cedar St., New Haven, CT 06520.

To whom correspondence should be addressed: University of Geneva Medical School, CMU, 1 rue Michel-Servet, CH-1211, Geneva, Switzerland. Tel.: 41-22-379-56-66; Fax: 41-22-379-57-46; E-mail: walter.reith{at}medecine.unige.ch.

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