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Vinexinβ, an atypical “sensor” of retinoic acid receptor γ signaling: union and sequestration, separation, and phosphorylation
Author(s) -
Lalevee Sébastien,
Bour Gaétan,
Quinternet Marc,
Samarut Eric,
Kessler Pascal,
Vitorino Marc,
Bruck Nathalie,
Delsuc MarcAndré,
Vonesch JeanLuc,
Kieffer Bruno,
RochetteEgly Cecile
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-160572
Subject(s) - phosphorylation , retinoic acid , chemistry , microbiology and biotechnology , receptor , signal transduction , biochemistry , biology , gene
The transcriptional activity of nuclear retinoic acid receptors (RARs) relies on the association/dissociation of coregulators at the ligand‐binding domain. However, we determined that the N‐terminal domain (NTD) also plays a role through its phosphorylation, and we isolated vinexinβ, a cytoskeleton protein with three SH3 domains, as a new partner of the RARγ NTD. Here we deciphered the mechanism of the interaction and its role in RARY‐mediated transcription. By combining molecular and biophysical (surface plasmon resonance, NMR, and fluorescence resonance energy transfer) approaches, we demonstrated that the third SH3 domain of vinexinβ interacts with a proline‐rich domain (PRD) located in RARγ NTD and that phosphorylation at a serine located in the PRD abrogates the interaction. The affinity of the interaction was also evaluated. In vivo , vinexinβ represses RARγ‐mediated transcription and we dissected the underlying mechanism in chromatin immunoprecipitation experiments performed with F9 cells expressing RARγ wild type or mutated at the phosphorylation site. In the absence of retinoic acid (RA), vinexinβ does not occupy RARγ target gene promoters and sequesters non‐phosphorylated RARγ out of promoters. In response to RA, RARγ becomes phosphorylated and dissociates from vinexinγ. This separation allows RARγ to occupy promoters. This is the first report of an RAR corepressor association/dissociation out of promoters and regulated by phosphorylation.—Lalevée, S., Bour, G., Quinternet, M., Samarut, E., Kessler, P., Vitorino, M., Bruck, N., Delsuc, M.‐A., Vonesch, J.‐L., Kieffer, B., Rochette‐Egly, C. Vinexinβ, an atypical “sensor” of retinoic acid receptor γ signaling: union and sequestration, separation, and phosphorylation. FASEB J . 24, 4523–4534 (2010). www.fasebj.org