IκBs exert principal functions as cytoplasmic inhibitors of NF-kB transcription factors. Additional roles for IκB homologues have been described, including chromatin association and transcriptional regulation. Phosphorylated and SUMOylated IκBα (pS-IκBα) binds to histones H2A and H4 in the stem cell and progenitor cell compartment of skin and intestine, but the mechanisms controlling its recruitment to chromatin are largely unknown. In a recent paper led by Lluís Espinosa at IMIM, the team showed that serine 32–36 phosphorylation of IκBα favors its binding to nucleosomes and demonstrate that p-IκBα association with H4 depends on the acetylation of specific H4 lysine residues. The N-terminal tail of H4 is removed during intestinal cell differentiation by proteolytic cleavage by trypsin or chymotrypsin at residues 17–19, which reduces p-IκBα binding. Inhibition of trypsin and chymotrypsin activity in HT29 cells increases p-IκBα chromatin binding but, paradoxically, impaired goblet cell differentiation, comparable to IκBα deletion. Taken together, the results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular basis for the understanding of the restricted nuclear distribution of p-IκBα in specific stem cell compartments.
In summary:
Nuclear IκBα preferentially binds the acetylated N-terminal tail of histone H4 in vivo, specifically in the skin and intestine stem cell compartments. N-terminal cleavage of histone H4 facilitates IκBα dissociation and cellular differentiation.
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- Nuclear IκBα binds the acetylated N-terminal tail of histone H4.
- The N-terminal tail of histone H4 is lost during cellular differentiation.
- Histone H4 cleavage is likely produced by Trypsin and Chymotrypsin.
- Cellular differentiation requires dynamic IκBα chromatin binding and dissociation.
Laura Marruecos, Joan Bertran, Daniel Álvarez-Villanueva, María Carmen Mulero, Yolanda Guillén, Luis G Palma, Martin Floor, Anna Vert, Sara Arce-Gallego, Irene Pecharroman, Laura Batlle, Jordi Villà-Freixa, Gourisankar Ghosh, Anna Bigas, Lluís Espinosa. Dynamic chromatin association of IκBα is regulated by acetylation and cleavage of histone H4. EMBO Reports (2021)22:e52649 2021 https://doi.org/10.15252/embr.202152649