Cyclosporine A is an uncompetitive inhibitor of proteasome activity and prevents NF‐κB activation

FEBS Letters

Meyer, Stephanie¹  Kohler, N.Gail¹  Joly, Alison¹ 

[1] CV Therapeutics, Inc., 3172 Porter Drive, Palo Alto, CA 94304, USA

关键词: Proteasome proteolysis;    NF-κB activation;    Cyclosporine A;    Immunosuppressant;    Inflammation;    ALLN;    N-acetyl-leucinyl-leucinyl-norleucinal;    CsA;    cyclosporine A;    LPS;    bacterial lipopolysaccharide;    MHC;    major histocompatability complex;    SDS-PAGE;    sodium dodecyl sulfate–polyacrylamide gel electrophoresis;    TNF;    tumor necrosis factor;   

DOI  :  10.1016/S0014-5793(97)00930-7

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Cyclosporine A is an immunosuppressive agent that is used clinically in the prevention of transplant rejection and development of graft-versus-host disease. Recently, cyclosporine A has been shown to possess anti-inflammatory properties and is capable of inhibiting lipopolysaccharide-induced NF-κB activation. Ubiquitin-mediated proteasomal proteolysis plays a critical role in signal-induced NF-κB activation since it regulates both IκB degradation and p105 processing, it is also involved in the production of peptides for the assembly of MHC class I molecules. We report here that cylcosporine A acts as an uncompetitive inhibitor of the chymotrypsin-like activity of the 20S proteasome in vitro and that it suppresses lipopolysaccharide-induced IκB degradation and p105 processing in vivo demonstrating that inhibition of proteasome proteolysis is the mechanism by which cyclosporine A prevents NF-κB activation. A structurally unrelated immunosuppressant, rapamycin, did not inhibit the 20S proteasome in vitro.

【 授权许可】

Unknown