Regulation of the human leukocyte‐derived arginine aminopeptidase endoplasmic reticulum‐aminopeptidase 2 gene by interferon‐γ

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Abstract
The leukocyte‐derived arginine aminopeptidase (L‐RAP) is the second aminopeptidase localized in the endoplasmic reticulum (ER) processing antigenic peptides presented to major histocompatibility complex (MHC) class I molecules. In this study, the genomic organization of the gene encoding human L‐RAP was determined and the regulatory mechanism of its expression was elucidated. The entire genomic structure of the L‐RAP gene is similar to both placental leucine aminopeptidase (P‐LAP) and adipocyte‐derived leucine aminopeptidase (A‐LAP) genes, confirming the close relationship of these three enzymes. Interferon (IFN)‐γ up‐regulates the expression of the L‐RAP gene. Deletion and site‐directed mutagenic analyses of the 5′‐flanking region of the L‐RAP gene and electrophoretic mobility shift assay indicated that while interferon regulatory factor (IRF)‐2 is important in the basal condition, IRF‐1 is the primary regulator of IFN‐γ‐mediated augmentation of the gene expression. In addition, PU.1, a member of the E26 transformation‐specific family of transcription factors, also plays a role in the regulation of gene expression. The maximum expression of the gene was achieved by coexpression of IRF‐1 and PU.1 in HEK293 cells and IRF‐2 suppressed the IRF‐1‐mediated enhancement of gene expression, suggesting that IFN‐γ‐induced L‐RAP gene expression is cooperatively regulated by IRFs and PU.1 transcription factors.