Differential activation of a C/EBP beta isoform by a novel redox switch may confer the lipopolysaccharide-inducible expression of interleukin-6 gene.
C/EBP beta, a member of the CCAAT/enhancer binding protein (C/EBP) family, is one of the key transcription factors responsible for the induction of a wide array of genes, some of which play important roles in innate immunity, inflammatory response, adipocyte and myeloid cell differentiation, and the acute phase response. Three C/EBP beta isoforms (i.e. LAP*, LAP, and LIP) were known to arise from differential translation initiation and display different functions in gene regulation. C/EBP beta is known to induce interleukin (IL)-6 gene when P388D1 cells are treated with lipopolysaccharide (LPS). Exactly how the transcriptional activities of C/EBP beta isoforms are involved in the regulation of the IL-6 gene remains unclear. Here we report that LPS-induced expression of IL-6 gene in P388D1 cells is mediated by a redox switch-activated LAP*. The intramolecular disulfide bonds of LAP* and LAP have been determined. Among the cysteine residues, amino acid 11 (Cys11) of LAP* plays key roles for determining the overall intramolecular disulfide bonds that form the basis for redox switch regulation. The DNA binding activity and transcriptional activity of LAP* are enhanced under reducing condition. LAP and LIP, lacking 21 and 151 amino acids, respectively, in the N-terminal region, are not regulated in a similar redox-responsive manner. Our results indicate that LAP* is the primary isoform of C/EBP beta that regulates, through a redox switch, the LPS-induced expression of the IL-6 gene.
Su
Wen-Chi
WC
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei.
Chou
Han-Yi
HY
Chang
Ching-Jin
CJ
Lee
Yu-May
YM
Chen
Wei-Hao
WH
Huang
Kuo-Hsiang
KH
Lee
Ming-Yue
MY
Lee
Sheng-Chung
SC
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D003545:Cysteine; D004220:Disulfides; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D020033:Protein Isoforms / Q000502:physiology; D017434:Protein Structure, Tertiary
D022782:CCAAT-Enhancer-Binding Protein-beta; D004220:Disulfides; D015850:Interleukin-6; D008070:Lipopolysaccharides; D020033:Protein Isoforms; D003545:Cysteine