Article
- The EMBO Journal (2008) 27, 1357 - 1367
- doi:10.1038/emboj.2008.73
Published online: 10 April 2008
Subject Categories:
NF-
B dictates the degradation pathway of IB
Erika Mathes1, Ellen L O'Dea1,2, Alexander Hoffmann1,2 and Gourisankar Ghosh1
- Department of Chemistry & Biochemistry, University of California, San Diego, La Jolla, CA, USA
- Signaling Systems Laboratory, Department of Chemistry & Biochemistry, University of California, San Diego, La Jolla, CA, USA
Correspondence to:
Alexander Hoffmann, Department of Chemistry & Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0375, USA. Tel.: +1 858 822 4670; Fax: +1 858 822 4671; E-mail: ahoffmann@ucsd.edu
Gourisankar Ghosh, Department of Chemistry & Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0375, USA. Tel.: +1 858 822 0469; Fax: +1 858 822 1408; E-mail: gghosh@ucsd.edu
Received 20 December 2007; Accepted 12 March 2008
Abstract
I
B proteins are known as the regulators of NF-B activity. They bind tightly to NF-B dimers, until stimulus-responsive N-terminal phosphorylation by IKK triggers their ubiquitination and proteasomal degradation. It is known that IB
is an unstable protein whose rapid degradation is slowed upon binding to NF-B, but it is not known what dynamic mechanisms control the steady-state level of total IB. Here, we show clearly that two degradation pathways control the level of IB. Free IB degradation is not controlled by IKK or ubiquitination but intrinsically, by the C-terminal sequence known as the PEST domain. NF-B binding to IB masks the PEST domain from proteasomal recognition, precluding ubiquitin-independent degradation; bound IB then requires IKK phosphorylation and ubiquitination for slow basal degradation. We show the biological requirement for the fast degradation of the free IB protein; alteration of free IB degradation dampens NF-B activation. In addition, we find that both free and bound IB are similar substrates for IKK, and the preferential phosphorylation of NF-B-bound IB is due to stabilization of IB by NF-B.
Keywords:
- degradation,
- IB,
- NF-B,
- proteasome
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