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6622.Full.Pdf Analysis of the Defect in IFN-γ Induction of MHC Class II Genes in G1B Cells: Identification of a Novel and Functionally Critical Leucine-Rich Motif This information is current as (62-LYLYLQL-68) in the Regulatory Factor of September 26, 2021. X 5 Transcription Factor W. June Brickey, Kenneth L. Wright, Xin-Sheng Zhu and Jenny P.-Y. Ting Downloaded from J Immunol 1999; 163:6622-6630; ; http://www.jimmunol.org/content/163/12/6622 References This article cites 62 articles, 36 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/163/12/6622.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 26, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Analysis of the Defect in IFN-g Induction of MHC Class II Genes in G1B Cells: Identification of a Novel and Functionally Critical Leucine-Rich Motif (62-LYLYLQL-68) in the Regulatory Factor X 5 Transcription Factor1 W. June Brickey,* Kenneth L. Wright,2* Xin-Sheng Zhu,† and Jenny P.-Y. Ting3* MHC class II deficiency found in bare lymphocyte syndrome patients results from the absence or dysfunction of MHC class II transcriptional regulators, such as regulatory factor X (RFX) and class II transactivator (CIITA). Understanding the roles of these factors has been greatly facilitated by the study of genetic defects in cell lines of bare lymphocyte syndrome patients, as well as in cell lines that have been generated by chemical mutagenesis in vitro. The latter group includes MHC class II-deficient lines that are no longer responsive to induction by IFN-g. Here, we show that the defect in G1B, one such cell line, is attributed to the lack Downloaded from of functional RFX5, the largest subunit of RFX. The RFX5 gene isolated from G1B cells contains two separate single-base pair mutations. One alteration does not exhibit a phenotype, whereas a leucine-to-histidine mutation eliminates DNA-binding and transactivating functions. This mutation lies outside of previously defined functional domains of RFX5 but within an unusual, leucine-rich region (62-LYLYLQL-68). To further investigate the significance of the leucine-rich region, we targeted all neigh- boring leucine residues for mutagenesis. These mutants were also unable to transactivate a MHC class II reporter gene, confirming http://www.jimmunol.org/ that these leucine residues play an essential role in RFX activity and characterize a novel leucine-rich motif. The Journal of Immunology, 1999, 163: 6622–6630. he IFN-g response of most genes requires a common cas- Ags. These include the invariant chain (Ii)4 (3) and the noncon- cade of activating proteins that regulate the induction of a ventional DM molecules. The expression of HLA-D, Ii, and DM T variety of genes. Many of these molecules have been well are in general synchronously regulated, and their levels fluctuate defined by biochemical and genetic approaches. However, the coordinately upon modulation (3–5). Their presence is restricted to IFN-g induction of MHC class II molecules requires additional APCs, such as B cells, macrophages, thymic epithelia, and acti- specific transcriptional activators. The strongest evidence for this vated T cells. Their level of expression is primarily regulated by by guest on September 26, 2021 requirement comes from the analyses of somatic mutant cell lines the activity of transcription factors (6–10). Therefore, understand- that are normal in their IFN-g responses except for the lack of ing the players and mechanisms of transcriptional regulation of induction of genes encoding MHC class II and associated mole- these genes will have significant biologic ramifications. cules (1, 2). This report focuses on the understanding of the mo- The MHC class II promoters as well as the Ii and DM promoters lecular and genetic basis for one such mutant cell line. are unique for the presence and stereochemical arrangement of The MHC class II molecules, HLA-D, play key regulatory roles three regulatory elements, the S/W, X, and Y (also known as a in T cell-mediated immune responses by presenting antigenic pep- CCAAT motif) elements (10–13). The factors that bind to X and tides on cell surfaces for recognition by class II-restricted T cells. Y boxes have been identified as the multimeric regulatory factor X Molecules other than the conventional MHC class II molecules are (RFX; Refs. 14 and 15) and trimeric nuclear factor Y (NF-Y) DNA required for optimal processing and presentation of a spectrum of binding proteins (16), respectively. An additional factor, known as X2 binding protein (X2BP), binds to the X2 element present in some promoters (17). Binding of factors to the X and Y elements serves novel roles, such as opening up previously closed promoters *UNC Lineberger Comprehensive Cancer Center and Department of Immunology and Microbiology and †Curriculum in Oral Biology, School of Dentistry, University in vivo and promoting accessibility to regulatory elements (18, 19). of North Carolina, Chapel Hill, NC 27599 Mutant cell lines that are defective in the expression of HLA-D Received for publication . Accepted for publication . molecules provide an important means for understanding the tran- The costs of publication of this article were defrayed in part by the payment of page scriptional regulation of MHC class II and related genes. These charges. This article must therefore be hereby marked advertisement in accordance systems include cells derived from patients afflicted with bare lym- with 18 U.S.C. Section 1734 solely to indicate this fact. phocyte syndrome (BLS), as well as cells generated in vitro by 1 This work was supported by National Institutes of Health Grants AI29564 and negative selection for the loss of HLA-D expression. The latter AI41580 to J. P.-Y. T.), and Multiple Sclerosis Society Grant RG1785 (to J. P.-Y. T.). W. J. B. was supported by National Institutes of Health Postdoctoral Training Grant includes both B cell lines that have lost constitutive MHC class II CA09156 and is the recipient of a National Kidney Foundation postdoctoral fellow- expression and IFN-g-defective cell lines that have selectively lost ship. K. L. W. is an Arthritis Foundation Fellowship awardee. the IFN-g induction of HLA-D expression (1, 20–23). The mutant 2 Present address: H. Lee Moffitt Cancer Center, Department of Biochemistry and Molecular Biology, University of South Florida, 12901 Magnolia Drive, Tampa, FL 33612. 4 Abbreviations used in this paper: Ii, invariant chain; RFX, regulatory factor X; 3 Address correspondence and reprint requests to Dr. Jenny P.-Y. Ting, UNC NF-Y, nuclear factor Y; X2BP, X2 binding protein; BLS, bare lymphocyte syndrome; Lineberger Comprehensive Cancer Center, Campus Box 7295, Room 209, University CIITA, class II transactivator; DBD, DNA binding domain; MMTV, mouse mam- of North Carolina, Chapel Hill, NC 27599-7295. E-mail address: panyun@med. mary tumor virus; CAT, chloramphenicol acetyltransferase; RT, reverse transcriptase; unc.edu wt, wild type; LRR, leucine-rich repeats. Copyright © 1999 by The American Association of Immunologists 0022-1767/99/$02.00 The Journal of Immunology 6623 EBV-transformed B cell lines fall into four complementation COOH. Each was conjugated to keyhole limpet hemocyanin before groups, and the genetic defects in all of these cell lines have been immunization. High titer antisera was subsequently purified by passage cataloged as defects either in the class II transactivator (CIITA) over protein A/G Sepharose columns as described by the manufacturer (Pierce, Rockford, IL). (24) or in the individual components of RFX (25, 26). To date, mutant cells defective in NF-Y have not been found, and this is EMSA, oligonucleotide competitions, and Ab supershift presumably due to the critical role NF-Y plays in the regulation of a large repertoire of CCAAT-containing promoters (19, 27, 28). Crude nuclear extracts were prepared as described (37). Gel-shift reactions were performed essentially as previously described (38), with slight mod- The focus of this study, RFX5, is defective in the complemen- ifications. Binding reactions (20 ml volume) were conducted in 12% glyc- tation group C of HLA-D-negative cell lines. The gene for RFX5 erol, 60 mM KCl, 12 mM HEPES (pH 7.9), 5 mM MgCl2, 0.06 mM was identified by complementation cloning using the BLS cell line EDTA, 0.5 mM DTT, and 0.5 mM PMSF with the nonspecific competitor SJO (25). RFX5 belongs to a family of novel DNA binding pro- mix of 1 mg poly(dI-dC) (Pharmacia, Piscataway, NJ) and 0.5 mg sheared teins, including among its members RFX1 to RFX4 (29). This salmon sperm DNA (Sigma, St. Louis, MO). To eliminate RFX5 family members that bind preferentially to methylated DNA, 50 ng of a high family shares an unusual and highly conserved DNA binding do- affinity methylated pBR322 oligonucleotide, 59-GATMGCMGTGAM main (DBD) (30, 31). It has been shown that RFX5 is the largest GATC-39 (where M 5 5-methyl cytosine), was included in each binding component, 75 kDa (3), of the multimeric nuclear complex RFX reaction.
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