MyD88S, a splice variant of MyD88, differentially modulates NF‐κB‐ and AP‐1‐dependent gene expression

FEBS Letters

Burns, Kim¹  Tschopp, Jurg¹  Beyaert, Rudi²  Vercammen, Elisabeth²  Janssens, Sophie² 

[1] Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveressses 155, CH-1066 Epalinges, Switzerland;Department of Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, Ghent University – VIB, Technologiepark 927, B-9052 Ghent, Belgium

关键词: MyD88;    c-Jun N-terminal kinase;    Interleukin-1 receptor-associated kinase;    Nuclear factor-κB;    Activator protein-1;    Toll/interleukin-1 receptor;    AP;    activator protein;    ID;    intermediate domain;    IL-1R;    interleukin-1 receptor;    IRAK;    IL-1R-associated kinase;    JNK;    c-Jun N-terminal kinase;    LPS;    lipopolysaccharide;    TIR;    Toll/interleukin-1 receptor;    TLR;    Toll-like receptor;    TRAF;    tumor necrosis factor receptor-associated factor;   

DOI  :  10.1016/S0014-5793(03)00747-6

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

MyD88 is an adapter protein that is involved in Toll-like receptor (TLR)- and interleukin-1 receptor (IL-1R)-induced activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK). By directly binding IL-1R-associated kinase (IRAK)-1 and IRAK-4, MyD88 serves as a bridging protein, enabling IRAK-4-induced IRAK-1 phosphorylation. We previously identified a lipopolysaccharide-inducible splice variant of MyD88, MyD88_S, which specifically prevents the recruitment of IRAK-4 into the IL-1R complex and thus inhibits IRAK-4-mediated IRAK-1 phosphorylation. MyD88_S is not able to activate NF-κB, and in contrast functions as a dominant negative inhibitor of TLR/IL-1R-induced NF-κB activation. Unexpectedly, we here demonstrate that MyD88_S still allows JNK phosphorylation and activator protein (AP)-1-dependent reporter gene induction upon overexpression in HEK293T cells. These observations indicate that NF-κB and JNK activation pathways can already diverge at the level of MyD88. Moreover, the regulated expression of a MyD88 splice variant which specifically interferes with NF-κB- but not AP-1-dependent gene expression implies an important role for alternative splicing in the fine-tuning of TLR/IL-1R responses.

【 授权许可】

Unknown