Functions of the Hsp90-Binding FKBP Immunophilins - The Networking of Chaperones by Co-chaperones - page 45

In a yeast model for studying functional interactions between steroid receptors
and human FKBPs, FKBP51 does not inhibit the activity of GR; however, FKBP51
can effectively reverse the potentiation of GR activity conferred by FKBP52 (Riggs
et al. 2003 ). Therefore, FKBP51 acts as an antagonist of FKBP52. FKBP51 has
also been shown to inhibit PR function (Hubler et al. 2003 ), presumably through
a similar inhibition of FKBP52-mediated potentiation. The mechanism by which
FKBP51 antagonizes FKBP52's ability to enhance steroid receptor function is not
understood. Other Hsp90-binding TPR proteins do not block FKBP52 actions, so
it does not appear that competitive displacement of FKBP52 from receptor com-
plexes by FKBP51 can fully account for antagonism. On the other hand, FKBP51
is known to preferentially associate with PR and GR complexes (Nair et al. 1997 ;
Barent et al. 1998 ). Domain swapping studies indicate that the FK1 PPIase domain
partially contributes to antagonism but sequences in the FK2 and TPR domain also
play a role (Riggs et al. 2003 ; Denny et al. 2005 ).
Given that FKBP51 gene expression is inducible by some steroid hormones and
FKBP51 can both activate and inhibit receptor function, one can reasonably specu-
late that FKBP51 serves as a cellular modulator of hormone responsiveness. In
cells unexposed to hormone, FKBP52 actions would predominate and promote a
robust response to hormone. As a consequence, FKBP51 levels would rise and par-
tially desensitize cells to a secondary hormone exposure in most systems excluding
AR-mediated prostate cancer cells. These effects can be demonstrated in cellular
models, but the physiological importance of this mechanism must be established
with animal models. Toward this goal, FKBP51 gene knockout (51KO) mice were
generated. Homozygous mutant animals are grossly normal and reproductively vi-
able, so FKBP51 does not appear to be critical in the same physiological processes
as FKBP52. Nonetheless, modulatory actions of FKBP51 are relevant but subject
to compensatory physiological mechanisms. Interestingly, double knockout of both
FKBP51 and FKBP52 genes is embryonic lethal in mice, suggesting either that
FKBP51 and FKBP52 have a critical, mutually redundant function or that FKBP51
and FKBP52 function in a common developmental pathway that requires the dis-
tinct actions of both immunophilins.
The hypothalamic-pituitary-adrenal (HPA) axis controls stress response and is
associated with susceptibility to depression as well as antidepressant efficacy (Tou-
ma et al. 2011 ; O'Leary et al. 2011 ). The HPA axis is regulated via negative feed-
back of GR activity and FKBP51. GR resistance is conferred by the overexpression
of FKBP51, which is associated with an impaired negative feedback mechanism
(Denny et al. 2005 ). Polymorphisms in the FKBP5 gene are associated with an
increased susceptibility for depression, an increased response to antidepressants,
and an increased risk of posttraumatic stress disorder in response to adverse early
life events (Binder et al. 2008 ; Binder et al. 2004 ). In addition, genotype-directed
environment-induced gene programming through FKBP5 gene methylation was re-
cently shown to mediate gene-childhood trauma interactions (Klengel et al. 2013 ).
Recent studies have shown that FKBP51 is a modulator of the cortisol-HPA axis
response to chronic stress and related psychiatric disorders (Hartmann et al. 2012 ;
O'Leary et al. 2011 ; Tatro et al. 2009 ; Touma et al. 2011 ). Indeed, 51KO mice