Differential recognition of canonical NF-κB dimers by Importin α3

• Published in: Nature communications Vol. 13; no. 1; p. 1207
• Main Authors: Florio, Tyler J., Lokareddy, Ravi K., Yeggoni, Daniel P., Sankhala, Rajeshwer S., Ott, Connor A., Gillilan, Richard E., Cingolani, Gino
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-03-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/45/612/1234; 631/535/1266; 631/80/389/2333; 82/16; 82/80; 82/83; beta Karyopherins - metabolism; Binding; Cell Nucleus - metabolism; Conformation; Cytoplasm; Dimers; Humanities and Social Sciences; Karyopherins - genetics; Karyopherins - metabolism; Localization; multidisciplinary; NF-kappa B - metabolism; NF-κB protein; Nuclear Localization Signals - metabolism; Nuclear transport; Science; Science (multidisciplinary); Signaling; Transcription; Translocation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28846-z

Nuclear translocation of the p50/p65 heterodimer is essential for NF-κB signaling. In unstimulated cells, p50/p65 is retained by the inhibitor IκBα in the cytoplasm that masks the p65-nuclear localization sequence (NLS). Upon activation, p50/p65 is translocated into the nucleus by the adapter importin α3 and the receptor importin β. Here, we describe a bipartite NLS in p50/p65, analogous to nucleoplasmin NLS but exposed in trans. Importin α3 accommodates the p50- and p65-NLSs at the major and minor NLS-binding pockets, respectively. The p50-NLS is the predominant binding determinant, while the p65-NLS induces a conformational change in the Armadillo 7 of importin α3 that stabilizes a helical conformation of the p65-NLS. Neither conformational change was observed for importin α1, which makes fewer bonds with the p50/p65 NLSs, explaining the preference for α3. We propose that importin α3 discriminates between the transcriptionally active p50/p65 heterodimer and p50/p50 and p65/65 homodimers, ensuring fidelity in NF-κB signaling.
Nuclear translocation of the p50/p65 heterodimer is essential for NF-κB signaling. Here, the authors identify a bipartite Nuclear Localization Signal in the NF-κB p50/p65 heterodimer that is recognized with high affinity by importin α3.