Volume 271, Number 33, Issue of August 16, 1996 pp. 20035-20046
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Interferon- Induction of the Human Leukocyte Antigen-E Gene Is Mediated through Binding of a Complex Containing STAT1 to a Distinct Interferon--responsive Element

(Received for publication, February 15, 1996, and in revised form, May 21, 1996)

From the Department of Medicine, Division of Oncology, Institute of Human Genetics and Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455

Expression of the human major histocompatibility complex (MHC) class I genes has been shown previously to increase at the transcriptional level following exposure to interferon- (IFN-). In this report we have examined the molecular mechanisms involved in the IFN--induced transcription of the human MHC class I gene, HLA-E. Functional analysis of CAT reporter gene constructs under the control of the HLA-E promoter transfected into U937 cells revealed the presence of a distinct IFN--responsive element, termed the interferon response region (IRR), that was necessary and sufficient to mediate the response to IFN-. This cis-acting regulatory sequence contains an imperfect inverted repeat; the 5-half of the IRR resembles the IFN- activation site (GAS), and the 3-half of the IRR resembles the interferon-stimulated response element (ISRE). Gel mobility shift assays demonstrated that the IRR bound a single, specific, IFN--induced complex (IRR-AC), which was formed rapidly following treatment with IFN- and was independent of protein synthesis. Competition experiments with GAS and ISRE sequences from other IFN-inducible genes showed that GAS sequences competed for the IRR-AC, whereas ISRE sequences did not compete. Mutational analysis demonstrated that point mutations in either the 5-half or 3-half of the IRR prevented binding of the complex and abrogated or markedly reduced the IFN- responsiveness of reporter gene constructs. Supershift analysis revealed that the IRR-AC contains a factor that was recognized by antibodies specific for the protein STAT1 (signal transducer and activator of transcription). Taken together, these findings suggest that the mechanism of IFN--induced transcription of the HLA-E gene is distinct from that of other MHC class I genes.

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