The serine/threonine phosphatase inhibitor calyculin A induces rapid degradation of IκBβ. Requirement of both the N- and C-terminal sequences

Edward Harhaj, Shao Cong Sun

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Abstract

Signal-initiated activation of the transcription factor NF-κB is mediated through proteolysis of its cytoplasmic inhibitory proteins IκBα and IκBβ. While most NF-κB inducers trigger the degradation of IκBα, only certain stimuli are able to induce the degradation of IκBβ. The degradation of IκBα is targeted by its site-specific phosphorylations, although the mechanism underlying the degradation of IκBβ remains elusive. In the present study, we have analyzed the effect of phosphatase inhibitors on the proteolysis of IκBβ. We show that the serine/threonine phosphatase inhibitor calyculin A induces the hyperphosphorylation and subsequent degradation of IκBβ in both human Jurkat T cells and the murine 70Z-3 preB cells, which is associated with the nuclear expression of active NF-κB. The calyculin A-mediated degradation of IκBβ is further enhanced by the cytoking tumor necrosis factor-α (TNF-α), although TNF-α alone is unable to induce the degradation of IκBβ. Mutational analyses have revealed that the inducible degradation of IκBβ induced by calyculin A, and TNF-α requires two N-terminal serines (serines 19 and 23) that are homologous to the inducible phosphorylation sites present in IκBα. Furthermore, the C- terminal 51 amino acid residues, which are rich in serines and aspartic acids, are also required for the inducible degradation signal of IκBβ may be controlled by the opposing actions of protein kinases and phosphotases and that both the N- and C-terminal sequences of IκBβ are required for the inducible degradation of this NF-κB inhibitor.

Original languageEnglish (US)
Pages (from-to)5409-5412
Number of pages4
JournalJournal of Biological Chemistry
Volume272
Issue number9
DOIs
StatePublished - Feb 28 1997

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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