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New Functions of the Major Histocompatibility Complex Class II-Specific Transcription Factor RFXANK Revealed by a High-Resolution Mutagenesis Study

Michal Krawczyk, Krzysztof Masternak, Madeleine Zufferey, Emmanuèle Barras, and Walter Reith^*

Department of Pathology and Immunology, University of Geneva Medical School, CMU, 1 rue Michel-Servet, CH-1211 Geneva, Switzerland

Received 9 March 2005/ Returned for modification 12 May 2005/ Accepted 14 July 2005

The transcription factors RFX and CIITA are major players in regulation of the expression of all classical and nonclassical major histocompatibility complex class II (MHC-II) genes. RFX nucleates the formation of a multiprotein complex, called the MHC-II enhanceosome, on MHC-II promoters. Assembly of this enhanceosome is an obligatory step for recruitment of the coactivator CIITA and thus for activation of MHC-II gene transcription. We have analyzed the function of the ankyrin repeat-containing protein RFXANK, which forms the heterotrimeric RFX complex together with RFX5 and RFXAP. We discovered that ANKRA2, the closest paralogue of RFXANK, can substitute for RFXANK in the activation of MHC-II genes and that this ability is mediated by its ankyrin repeat domain (ARD). This finding provided the basis for a high-resolution structure-function analysis of the ARD of RFXANK, which allowed us to map the RFX5 interaction domain and residues critical for assembly of the RFX complex. We also found that mutations in the fourth ankyrin repeat of RFXANK abolish assembly of the enhanceosome on MHC-II promoters in vivo but not in vitro, suggesting a new role of RFXANK in facilitating promoter occupation in the context of chromatin.

Present address: NovImmune SA, CH-1211 Geneva, Switzerland.

Present address: Department of Microbiology and Molecular Medicine, University of Geneva Medical School, CMU, CH-1211 Geneva, Switzerland.

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