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- Title
Functional Analysis of a Dominant Negative Mutation of Interferon Regulatory Factor 5.
- Authors
Long Yang; Tiejun Zhao; Xiaoliu Shi; Nakhaei, Peyman; Yunling Wang; Qiang Sun; Hiscott, John; Rongtuan Lin
- Abstract
Background: Interferon regulatory factor (IRF) family members have been implicated as critical transcription factors that function in immune response, hematopoietic differentiation and cell growth regulation. Activation of IRF-5 results in the production of pro-inflammatory cytokines such as TNFα, IL6 and IL12p40, as well as type I interferons. Methodology/Principal Findings: In this study, we identify a G202C (position relative to translation start codon) missensemutation transcript of IRF-5 in transformed B and T cell lines, which were either infected or non-infected by viruses, and peripheral blood from ATL or CLL patients. The mutated transcript encodes a novel protein in which the sixty-eighth amino acid, Alanine, is substituted by Proline (IRF-5P68) in the DNA binding domain of IRF-5. IRF-5P68 phenotype results in a complete loss of its DNA-binding activity and functions as a dominant negative molecule through interacting with wild type IRF-5. Co-expression of IRF-5P68 inhibits MyD88-mediated IRF-5 transactivation. Moreover, Toll-like receptor (TLR)- dependent IL6 and IL12P40 production induced by lipopolysaccharide (LPS), R837 or CpG ODN 1826 was reduced in IRF-5 (P68) expressing cells as compared to the control cells. Conclusion: IRF-5P68 acts as a dominant negative regulator that interferes with IRF-5-mediated production of proinflammatory cytokines. The functional characterization of the novel IRF-5 mutant in transformed B and T cell lines and in ATL and CLL patients may lead to a better understanding of the role of these transcriptional regulators in hematopoietic malignancies.
- Subjects
FUNCTIONAL analysis; GENETIC mutation; INTERFERONS; IMMUNE response; TRANSCRIPTION factors; HEMATOPOIETIC growth factors; CYTOKINES; CELL lines; B cells; T cells
- Publication
PLoS ONE, 2009, Vol 4, Issue 5, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0005500