Functional redundancy of transcription factor-binding sites in the killer cell Ig-like receptor (KIR) gene promoter.

TitleFunctional redundancy of transcription factor-binding sites in the killer cell Ig-like receptor (KIR) gene promoter.
Publication TypeJournal Article
Year of Publication2006
JournalInternational immunology
Volume18
Issue8
Pagination1221-32
Date Published2006 Aug
ISSN0953-8178
AbstractVariegated expression of inhibitory killer cell Ig-like receptors (KIRs) for MHC class I molecules helps NK cells distinguish normal from aberrant self and avoid autoreactivity. Prior studies of KIR promoters have produced conflicting results and no cis-acting sites have been independently confirmed. We took a comprehensive linker-scanning mutagenesis approach and substituted 24 consecutive 10-bp segments in the human KIR3DL1 promoter. Our analysis revealed eight segments that activated and three segments that repressed KIR transcription. Site-directed mutagenesis and electrophoretic mobility shift assays indicated that optimal KIR transcription requires a proximal Ets site that binds several Ets family members, a cAMP response element (CRE), a Runx site and a site that mediates complex interactions between Ets family members, signal transducer and activator of transcription 5 (STAT5) and YY1; Sp1 also contributes to KIR transcription. KIR transcription was greatly reduced by several compound mutations and was abrogated by a combination of mutations that affected the proximal Ets site, and the CRE, Runx, Sp1 and Ets/STAT sites. The many transcription factors that contribute to KIR transcription are partially redundant in the setting of transient transfection assays, helping to explain why only 0-2 activating sites had been reported in each of three prior studies. We propose that the multiplicity of transcription factors enables NK cells to sustain continuous KIR expression in diverse cellular and cytokine milieus, thus preventing NK autoreactivity.
URLhttps://academic.oup.com/intimm/article-lookup/doi/10.1093/intimm/dxl043
DOI10.1093/intimm/dxl043
PubMed Linkhttp://www.ncbi.nlm.nih.gov/pubmed/16818466?dopt=Abstract
Short TitleInt Immunol