Hsp90-binding TPR proteins regulate the subcellular localization of nuclear factors

GALIGNIANA MD, GALLOLI, ECHEVERRÍAPC, ERLEJMAN AG, PIWIEN PILIPUK G

DUBROVNIK, CROACIA

Conferencia; EMBO-The Biology of Molecular Chaperones; 2009

EMBO

Tetratricopeptide repeats (TPR) are degenerative sequences of 34 amino acids that are involved in a variety of protein-protein interactions. The molecular chaperone machinery contains multiple protein components that have at least one TPR motif bound to the MEEVD core of the common acceptor site located at the C-terminal end of hsp90. Among the best-characterized TPR proteins are several cochaperones (Hop, FKBP52, FKBP51, CyP40, PP5, XAP2, etc.) that participate in the assembly and functional regulation of steroid receptor (SR) complexes, the first recognized native clients for TPR proteins. In our laboratory we study the biological relevance of these associations. In previous works, we reported that the hsp90•FKBP52•dynein complex favors the retrotransport of SRs. Here, we show that the SR is still bound to that complex during the first minutes in the nuclear compartment, and also demonstrate that transformation (hsp90 dissociation) is a nuclear event. One logical prediction of this model is that proteins belonging to the cytoplasmic form of the SR oligomer should interact with components of the nuclear pore complex. Such interface is demonstrated for several nucleoporins by confocal microscopy, coimmunoprecipitation assays of native complexes and reconstitution assays. In the nucleus, FKBP52 remains associated to the receptor on the nucleoskeleton via NuMA. Competition with other TPR proteins or the TPR peptide itself disrupts the SR•FKBP52 interaction making the SR soluble in the nucleoplasm and (consequently?) more rapidly exported to the cytoplasm. Even though FKBP52-/- cells still show the SR in nuclear foci associated to the nucleoskeleton, the requirements to extract the SR from nuclei are significantly weaker than for FKBP52 expressing cells. Most of the results described here for SRs are also shown for other hsp90•TPR protein-interacting nuclear factor such as p53. Taken together, these observations demonstrate that TPR proteins regulate the subcellular localization and consequently, the biological functions, of TPR-binding nuclear factors. Because some of these TPR cochaperones are already known drug targets, there is a reasonable prospect for future drugs and molecular therapies that will target individual TPR cochaperones as a means of enhancing or inhibiting cellular processes.