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NF‐κB dictates the degradation pathway of IκBα
Author(s) -
Mathes Erika,
O'Dea Ellen L,
Hoffmann Alexander,
Ghosh Gourisankar
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2008.73
Subject(s) - phosphorylation , ubiquitin , biology , iκb kinase , iκbα , microbiology and biotechnology , nf κb , degradation (telecommunications) , protein degradation , biochemistry , signal transduction , telecommunications , computer science , gene
IκB proteins are known as the regulators of NF‐κB activity. They bind tightly to NF‐κB dimers, until stimulus‐responsive N‐terminal phosphorylation by IKK triggers their ubiquitination and proteasomal degradation. It is known that IκBα is an unstable protein whose rapid degradation is slowed upon binding to NF‐κB, but it is not known what dynamic mechanisms control the steady‐state level of total IκBα. Here, we show clearly that two degradation pathways control the level of IκBα. Free IκBα degradation is not controlled by IKK or ubiquitination but intrinsically, by the C‐terminal sequence known as the PEST domain. NF‐κB binding to IκBα masks the PEST domain from proteasomal recognition, precluding ubiquitin‐independent degradation; bound IκBα then requires IKK phosphorylation and ubiquitination for slow basal degradation. We show the biological requirement for the fast degradation of the free IκBα protein; alteration of free IκBα degradation dampens NF‐κB activation. In addition, we find that both free and bound IκBα are similar substrates for IKK, and the preferential phosphorylation of NF‐κB‐bound IκBα is due to stabilization of IκBα by NF‐κB.