Cell-Specific Association and Shuttling of IκBα Provides a Mechanism for Nuclear NF-κB in B Lymphocytes

Abstract

Mature B lymphocytes are unique in containing nuclear Rel proteins prior to cell stimulation. This activity consists largely of p50–c-Rel heterodimers, and its importance for B-cell function is exemplified by reduced B-cell viability in several genetically altered mouse strains. Here we suggest a mechanism for the cell specificity and the subunit composition of constitutive B-cell NF-κB based on the observed properties of Rel homo- and heterodimers and IκBα. We show that c-Rel lacks a nuclear export sequence, making the removal of c-Rel-containing complexes from the nucleus less efficient than removal of p65-containing complexes. Second, the nuclear import potential of p65 and c-Rel homodimers but not p50-associated heterodimers was attenuated when they were complexed to IκBα, leading to a greater propensity of heterodimers to be nuclear. We propose that subunit composition of B-cell NF-κB reflects the inefficient retrieval of p50–c-Rel heterodimers from the nucleus. Cell specificity may be a consequence of c-Rel–IκBα complexes being present only in mature B cells, which leads to nuclear c-Rel due to IκBα turnover and shuttling of the complex.

ACKNOWLEDGMENTS

The human CRM1 gene and LMB were kindly provided by G. Grosveld and M. Yoshida (University of Tokyo), respectively. We thank Phil Gnatowski for help in preparation of the manuscript.

This work was supported by NIH grant AI-41035 to R.S.