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Differential IFN- Stimulation of HLA-A Gene Expression through CRM-1-Dependent Nuclear RNA Export¹

Sarah K. Browne^2,*, James R. Roesser^*,, Sheng Zu Zhu^* and Gordon D. Ginder^3,*,,,¶

^* Massey Cancer Center, Virginia Commonwealth University Medical Center, Richmond, VA 23298; and Department of Biochemistry, Department of Internal Medicine, Department of Microbiology and Immunology, and ^¶ Department of Human Genetics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298

IFNs regulate most MHC class I genes by stimulating transcription initiation. As shown previously, IFN- controls HLA-A expression primarily at the posttranscriptional level. We have defined two 8-base sequences in a 39-nucleotide region in the 3'-transcribed region of the HLA-A gene that are required for the posttranscriptional response to IFN-. Stimulation of HLA-A expression by IFN- requires nuclear export of HLA-A mRNA by chromosome maintenance region 1 (CRM-1). Treatment of cells with leptomycin B, a specific inhibitor of CRM-1, completely inhibited IFN- induction of HLA-A. Expression of a truncated, dominant-negative form of the nucleoporin NUP214/CAN, CAN, that specifically interacts with CRM-1, also prevented IFN- stimulation of HLA-A, providing confirmation of the role of CRM-1. Increased expression of HLA-A induced by IFN- also requires protein methylation, as shown by the fact that treatment of SK-N-MC cells or HeLa cells with the PRMT1 inhibitor 5'-methyl-5'-thioadenosine abolished the cellular response to IFN-. In contrast with HLA-A, IFN--induced expression of the HLA class Ib gene, HLA-E, was not affected by either 5'-methyl-5'-thioadenosine or leptomycin B. These results provide proof of principle that it is possible to differentially modulate the IFN--induced expression of the HLA-E and HLA-A genes, whose products often mediate opposing effects on cellular immunity to tumor cells, pathogens, and autoantigens.

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 This work was supported by National Cancer Institute Grant CA87496 (to G.D.G.) and by the Massey Cancer Center, Virginia Commonwealth University.

² Current address: Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115.

³ Address correspondence and reprint requests to Dr. Gordon D. Ginder, Massey Cancer Center, 401 College Street, P.O. Box 980037, Richmond, VA 23298-0037. E-mail address: gdginder{at}vcu.edu

⁴ Abbreviations used in this paper: MHC-I, MHC class I; MHC-Ia, MHC-I class Ia; ISRE, IFN-stimulated response element; IRF-1, IFN regulatory factor 1; IRR, IFN response region; UIRR, upstream IRR; nt, nucleotide; LMB, leptomycin B; CRM-1, chromosome maintenance region 1; MTA, 5'-methyl-5'-thioadenosine; Tta, Tet transactivator protein; NES, nuclear export sequence; hnRNPA1, heteronuclear ribonucleoprotein A1.