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Molecular and Cellular Biology, August 2002, p. 5616-5625, Vol. 22, No. 15
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.15.5616-5625.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Major Histocompatibility Complex Class II Transcriptional Platform: Assembly of Nuclear Factor Y and Regulatory Factor X (RFX) on DNA Requires RFX5 Dimers

Nabila Jabrane-Ferrat,1 Nada Nekrep,2,3,4 Giovanna Tosi,2,3 Laura J. Esserman,1 and B. Matija Peterlin2,3*

Departments of Surgery,,1 Medicine, and,2 Microbiology and Immunology, University of California San Francisco, San Francisco, California 94115-0703,3 Institute of Biochemistry, Medical Faculty of the University of Ljubljana, 1000 Ljubljana, Republic of Slovenia4

Received 31 October 2001/ Returned for modification 23 January 2002/ Accepted 16 April 2002

Major histocompatibility complex class II (MHC-II) genes are regulated in a B-cell-specific and gamma interferon-inducible manner. Conserved upstream sequences (CUS) in their compact promoters bind nuclear factor Y (NFY) and regulatory factor X (RFX) complexes. These DNA-bound proteins form a platform that attracts the class II transactivator, which initiates and elongates MHC-II transcription. In this report, we analyzed the complex assembly of these DNA-bound proteins. First, we found that NFY can interact with RFX in cells. In particular, NFYA and NFYC bound RFXANK/B in vitro. Next, RFX5 formed dimers in vivo and in vitro. Within a leucine-rich stretch N-terminal to the DNA-binding domain in RFX5, the leucine at position 66 was found to be critical for this self-association. Mutant RFX5 proteins that could not form dimers also did not support the formation of higher-order DNA-protein complexes on CUS in vitro or MHC-II transcription in vivo. We conclude that the MHC-II transcriptional platform begins to assemble off CUS and then binds DNA via multiple, spatially constrained interactions. These findings offer one explanation of why in the Bare Lymphocyte Syndrome, which is a congenital severe combined immunodeficiency, MHC-II promoters are bare when any subunit of RFX is mutated or missing.

* Corresponding author. Mailing address: N215, UCSF Mt. Zion Cancer Center, 2340 Sutter St., San Francisco, CA 94115-0703. Phone: (415) 502-1902. Fax: (415) 502-1901. E-mail: matija{at}itsa.ucsf.edu.

Molecular and Cellular Biology, August 2002, p. 5616-5625, Vol. 22, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.15.5616-5625.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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