Divergent actions of Hsp90-binding immunophilins on the neurotrophic effect

DANERI-BECERRA, CRISTINA; LOTUFO, CECILIA; ROSBACO, EMILIA; GALIGNIANA, MARIO; RAMOS HRYB ANA BELÉN; ZGAJNAR, NADIA

San Diego

Congreso; NinthInternational Congress on Stress Responses in Biology and Medicine; 2019

Cell Stress Society International.

Immunophilins are a family of proteins that show intrinsic peptidyl-prolyl isomerase activity and bind immunosuppressive drugs. They are classified as FK506-binding proteins (FKBPs) when they bind the macrolide FK506 (tacrolimus), or cyclophilins (CyPs) when they bind the cyclic undecapeptide cyclosporine A (CsA). Only the low molecular weight immunophilins FKBP12 (12-kDa) and CyPA (17-kDa) mediate immunosuppression when they bind the cognate ligand. High molecular weight immunophilins also possess tetratricopeptide repeats (or TPR domains) through which they bind Hsp90, and via this chaperone, immunophilins associate to various Hsp90 client-proteins such as steroid receptors, tyrosine kinases, p53, telomerase, NOS, cofactors, etc. Our laboratory has demonstrated that both FKBP51 (51-kDa) and FKBP52 (52-kDa) are Hsp90-binding immunophilins belonging to the Hsp90?Hsp70?p23-based chaperone oligomer associated to steroid receptors, a heterocomplex where both immunophilins play key roles in receptor trafficking, nuclear translocation, transcriptional regulation, and nuclear export. In this study, we discuss our recent advances on the Hsp90-binding immunophilin function related to neurodifferentiation and neuroregeneration. Both undifferentiated neuroblastoma cell lines and primary cultures of embryonic hippocampal cells acquire neuronal phenotype upon exposure to the immunophilin ligand FK506 in a medium lacking any trophic factor, including serum. The rapid acquisition of a neuronal phenotype is accompanied by increased expression of typical neuronal markers (βIII-tubulin, Map2, Tau-1) and the chaperones Hsp90, Hsp70, p23, and FKBP52, whereas FKBP51 remains stable. Interestingly, confocal microscopy images show that the FKBP52?Hsp90?p23 heterocomplex concentrates in perinuclear structures associated to nuclear lamin. FK506 makes the chaperones of the annular structures to be rapidly redistributed throughout the cytoplasm, FKBP52 being concentrated at the axonal ends and ramification points, and Hsp70 and FKBP51 being recruited to those areas where the chaperone ring was first located. While neurite outgrowth is favoured by either FKBP52 overexpression or FKBP51 knock-down, it is accordingly impaired by FKBP52 knock-down or FKBP51 overexpression. This suggests that the FKBP52/FKBP51 expression balance plays a positive role during the early steps of neuronal differentiation. Similar results are achieved when axons are dissected and the cells are reincubated with FK506. All these observations performed in vitro show perfect parallelism with in vivo murine models subjected to spinal cord injury or prefrontal brain cortex damage, and treated with FK506. Compared to wild type mice, the recovery of the locomotor activity is faster in FKBP51 KO mice, and is abrogated in FKBP52 KO mice. Similar studies were also performed in Drosophila models where dFKBP59, the ortholog gene for FKBP52, was knocked-out. After wind nerve section followed by FK506 treatment, the effects of axonal degeneration and post-injury inflammatory reaction are reverted.In conclusion, we conclude that the Hsp90-binding immunophilins FKBP51 and FKBP52 are novel key factors of the neurotrophic phenomenon and propose that this mechanism may be affected in different areas of the nervous system according to the expression balance of these two immunophilins. Importantly, these studies suggest that specific immunophilin ligands could be beneficial for both processes, neurodifferentiation and neuroregeneration.