Cell-specific association and shuttling of IkappaBalpha provides a mechanism for nuclear NF-kappaB in B lymphocytes.
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-kappaB based on the observed properties of Rel homo- and heterodimers and IkappaBalpha. 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 IkappaBalpha, leading to a greater propensity of heterodimers to be nuclear. We propose that subunit composition of B-cell NF-kappaB reflects the inefficient retrieval of p50-c-Rel heterodimers from the nucleus. Cell specificity may be a consequence of c-Rel-IkappaBalpha complexes being present only in mature B cells, which leads to nuclear c-Rel due to IkappaBalpha turnover and shuttling of the complex.
Tam
W F
WF
Rosenstiel Basic Medical Sciences Research Center and Department of Biology, Brandeis University, Waltham, Massachusetts 02454, USA.
Wang
W
W
Sen
R
R
D001402:B-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D020569:Proto-Oncogene Proteins c-rel; D011993:Recombinant Fusion Proteins; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha