NF-kB is modulated by FK506-binding proteins FKBP51 and FKBP52 in an opposite manner

ERLEJMAN AG, DE LEO SA, CAMISAY MF, MAZAIRA GI, GALIGNIANA MD

Montevideo

Conferencia; First International Conference of the South American Chapter of the Cell Stress Society International; 2014

Cell Stress Society International

Nuclear factor kB (NF-kB) is a transcription factor involved in stress-induced, immune, and inflammatory responses. Canonical NF-kB is a heterodimer of p65/RelA with p50 subunits placed inactive in the cytoplasm bound to IkB. NF-kB activation causes IkB phosphorylation, its dissociation, and NF-kB nuclear translocation. In previous studies, we have shown that FK506-binding proteins (FKBPs) FKBP51 and FKBP52 modulate both trafficking and transcriptional activity of steroid receptors. These immunophilins have two key sequences, the TPR domain, through which they usually bind to Hsp90; and the peptidylprolyl-isomerase (PPIase) domain, where the immunosuppressant drug FK506 binds. The aim of this work was to investigate if FKBP51 and FKBP52 are able to modulate NF-kB properties as they do with steroid receptors. While FKBP51 overexpression impairs both the nuclear translocation rate of p65/RelA and NF-kB transcriptional activity, FKBP52 overexpression does not affect retrotransport, but increases p65/RelA nuclear retention time, favors its binding to DNA consensus sequences, and also transcriptional activity. The latter property is an entirely dependent effect on the PPIase activity of FKBP52. In resting cells, FKBP51 co-immunoprecipitates with the p65/RelA. Upon cell stimulation with phorbol esters, NF-kB exchanges FKBP51 by FKBP52 in the complex. In contrast to steroid receptors, this protein exchange appears independent of the presence of Hsp90. Competition assays demonstrate that the binding of both co-chaperones appears to be direct and antagonize one another. Therefore, we conclude that the biological activity of NF-kB is favored by a higher FKBP52/FKBP51 ratio. This is the first evidence showing that the balance of the cell expression for both immunophilins modulate NF-kB function in an opposite manner. Also, this is the firat evidence that endogenous immunophilins are recruited to DNA consensus sequences of NF-kB-commanded genes.