Regulation of RelA subcellular localization by a putative nuclear export signal and p50.
Nuclear factor kappaB (NF-kappaB) represents a family of dimeric DNA binding proteins, the pleotropic form of which is a heterodimer composed of RelA and p50 subunits. The biological activity of NF-kappaB is controlled through its subcellular localization. Inactive NF-kappaB is sequestered in the cytoplasm by physical interaction with an inhibitor, IkappaBalpha. Signal-mediated IkappaBalpha degradation triggers the release and subsequent nuclear translocation of NF-kappaB. It remains unknown whether the NF-kappaB shuttling between the cytoplasm and nucleus is subjected to additional steps of regulation. In this study, we demonstrated that the RelA subunit of NF-kappaB exhibits strong cytoplasmic localization activity even in the absence of IkappaBalpha inhibition. The cytoplasmic distribution of RelA is largely mediated by a leucine-rich sequence homologous to the recently characterized nuclear export signal (NES). This putative NES is both required and sufficient to mediate cytoplasmic localization of RelA as well as that of heterologous proteins. Furthermore, the cytoplasmic distribution of RelA is sensitive to a nuclear export inhibitor, leptomycin B, suggesting that RelA undergoes continuous nuclear export. Interestingly, expression of p50 prevents the cytoplasmic expression of RelA, leading to the nuclear accumulation of both RelA and p50. Together, these results suggest that the nuclear and cytoplasmic shuttling of RelA is regulated by both an intrinsic NES-like sequence and the p50 subunit of NF-kappaB.
Harhaj
E W
EW
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey Medical Center, Hershey, Pennsylvania 17033, USA.
Sun
S C
SC
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002451:Cell Compartmentation; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D028884:Karyopherins; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000302:isolation & purification / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D018160:Receptors, Cytoplasmic and Nuclear; D051996:Transcription Factor RelA; D000097606:Exportin 1 Protein
D002352:Carrier Proteins; D005231:Fatty Acids, Unsaturated; D028884:Karyopherins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D018160:Receptors, Cytoplasmic and Nuclear; D051996:Transcription Factor RelA; D000097606:Exportin 1 Protein; C038753:leptomycin B