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Molecular and Cellular Biology, June 2004, p. 4895-4908, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4895-4908.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Regulation of Constitutive p50/c-Rel Activity via Proteasome Inhibitor-Resistant IB Degradation in B Cells

Program in Cellular and Molecular Biology, Department of Pharmacology,¹ Department of Biochemistry, University of Wisconsin—Madison, Madison, Wisconsin 53706²

Received 30 November 2003/ Returned for modification 21 January 2004/ Accepted 2 March 2004

Constitutive NF-B activity has emerged as an important cell survival component of physiological and pathological processes, including B-cell development. In B cells, constitutive NF-B activity includes p50/c-Rel and p52/RelB heterodimers, both of which are critical for proper B-cell development. We previously reported that WEHI-231 B cells maintain constitutive p50/c-Rel activity via selective degradation of IB that is mediated by a proteasome inhibitor-resistant, now termed PIR, pathway. Here, we examined the mechanisms of PIR degradation by comparing it to the canonical pathway that involves IB kinase-dependent phosphorylation and ß-TrCP-dependent ubiquitylation of the N-terminal signal response domain of IB. We found a distinct consensus sequence within this domain of IB for PIR degradation. Chimeric analyses of IB and IBß further revealed that the ankyrin repeats of IB, but not IBß, contained information necessary for PIR degradation, thereby explaining IB selectivity for the PIR pathway. Moreover, we found that PIR degradation of IB and constitutive p50/c-Rel activity in primary murine B cells were maintained in a manner different from B-cell-activating-factor-dependent p52/RelB regulation. Thus, our findings suggest that nonconventional PIR degradation of IB may play a physiological role in the development of B cells in vivo.

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