Immunosuppressant FK506 Activates NF- Kappa B through the Proteasome-mediated Degradation of I Kappa B alpha . Requirement for I Kappa B alpha N-Terminal Phosphorylation but not Ubiquitination Sites

The immunosuppressant FK506 activates NF- Kappa B through I Kappa B alpha degradation in nonlymphoid cells. In the present study, we analyzed mechanisms by which FK506 induces I Kappa B alpha degradation. We found that FK506 induces the degradation of both I Kappa B alpha and I Kappa B beta and that...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-12, Vol.274 (49), p.34657-34662
Main Authors: Zhang, Y, Sun, X, Muraoka, K, Ikeda, A, Miyamoto, S, Shimizu, H, Yoshioka, K, Yamamoto, K
Format: Article
Language:English
Subjects:
FK506
IBa protein
IBb protein
NF-B protein
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Summary:The immunosuppressant FK506 activates NF- Kappa B through I Kappa B alpha degradation in nonlymphoid cells. In the present study, we analyzed mechanisms by which FK506 induces I Kappa B alpha degradation. We found that FK506 induces the degradation of both I Kappa B alpha and I Kappa B beta and that the time courses of the FK506- induced degradation are quite different from degradation induced by interleukin 1 (IL-1). Despite this difference, FK506-induced I Kappa B alpha degradation was dependent on the N-terminal Ser-32 and Ser-36 phosphorylation sites and was mediated by proteasomes, as is the case for IL-1- induced I Kappa B alpha degradation. We further showed that FK506 induces weak and slow phosphorylation of I Kappa B alpha at Ser-32. However, unlike IL-1-induced degradation, IKK-1 and IKK-2 were not activated significantly nor was FK506-induced I Kappa B alpha degradation dependent on the N-terminal ubiquitination sites (Lys-21 and Lys-22). These results therefore indicate that FK506 and IL-1 utilize similar but distinct mechanisms to induce the phosphorylation and degradation of I Kappa B alpha .
ISSN:0021-9258
DOI:10.1074/jbc.274.49.34657