An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of Ikappa Balpha

Abstract

The potent transcriptional activities of Rel/NF-κB proteins are regulated in the cytoplasm and nucleus by the inhibitor, IκBα. The mechanism, by which IκBα can either sequester NF-κB in the cytoplasm or act as a nuclear post-induction repressor of NF-κB, is uncertain. We find that IκBα shuttles continuously between the nucleus and cytoplasm. This shuttling requires a previously unidentified CRM1-dependent nuclear export signal (NES) located within the N-terminal domain of IκBα at amino acids 45-55. Deletion or mutation of the N-terminal NES results in nuclear localization of IκBα. NF-κB (p65) association with IκBα affects steady-state localization but does not inhibit its shuttling. Endogenous complexes of IκBα-NF-κB shuttle and will accumulate in the nucleus when CRM1 export is blocked. We find TNFα can activate the nuclear IκBα-NF-κB complexes by the classical mechanism of proteasome-mediated degradation of IκBα. These studies reveal a more dynamic nucleocytoplasmic distribution for IκBα and NF-κB suggesting previously unknown strategies for regulating this ubiquitous family of transcription activators.

Subcellular localization and nucleocytoplasmic transport of the chromosomal passenger proteins before nuclear envelope breakdown

“…endogenous NF-kB, whose cytoplasmic localization requires active CRM1-dependent export from the nucleus (Johnson et al, 1999), confirmed the effective blockage of CRM1 in these cells. In line with the lack of LMB responsiveness, the fraction of Borealin localized in the nucleus did not undergo relocation to the cytoplasm when coexpressed with YFP-CRM1 ( Figure 3c).…”

Wedelolactone suppresses LPS-induced caspase-11 expression by directly inhibiting the IKK Complex

“…14 The subcellular location of NF-kB is controlled by a family of inhibitory proteins, IkBs, such as IkBa, which bind NF-kB to maintain the cytoplasmic localization of NF-kB in unstimulated cells. 14 Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IkBa, which allows the nuclear translocation of NF-kB where it binds to DNA and regulates gene transcription.…”

“…14 Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of IkBa, which allows the nuclear translocation of NF-kB where it binds to DNA and regulates gene transcription. 11,14 Both LPS and TNFa induce NF-kB transcriptional activity through the degradation of the inhibitor IkB. These external signals act through their respective receptors to activate the IkB kinase (IKK) complex, which contains the catalytic subunits IKKa and IKKb, and the regulatory subunit IKKg/ NEMO.…”

Nuclear bcl10 expression characterizes a group of ocular adnexa MALT lymphomas with shorter failure-free survival

“…IkB-a is a physiological ligand of NF-kB in the cytoplasm, whose phosphorylation permits the liberation and migration of NF-kB into the nucleus, where NF-kB plays its transcriptional role, upregulating the expression of antiapoptotic proteins. 7,[27][28][29][30] In MALT lymphoma, deregulation of the expression of MALT1 gene due to chromosomal translocations t(11;18)(q21; q21) and t(14;18)(q32;q21) seems to be one of the main pathogenic mechanisms leading to reduced apoptotic activity. 12,15,22,[31][32][33] In contrast to what has been described in gastric MALT lymphomas, our results did not indicate the presence of t (11;18).…”