steroid hormone receptors mediate hormone signaling by acting as ligand dependent transcription factors .   upon ligand binding , these receptors undergo conformational changes that are coupled with specific interactions with transcriptional co - factors and/or nuclear translocation , culminating with induction of specific transcriptional programs that control diverse processes from homeostasis and growth , to reproduction , development and metabolism 
					 [ robinson - rechavi et al . , 2003 ; 
					 gronemeyer et al . , although ligand binding is the primary regulatory signal for receptor activation , selected members of the steroid hormone receptor family require additional cellular machinery to achieve a conformation capable of responding to ligand . extensive biochemical reconstitution and functional analysis of glucocorticoid receptor ( gr ) have revealed an obligatory role for the molecular chaperone hsp90 in gr structural maturation and function 
					 [ pratt et al . , 1992 ; 
					 pratt et al . , it has been proposed that gr is normally associated with the hsp90 chaperone complex in the cytoplasm prior to ligand binding . this association allows gr to achieve a structural conformation that is competent for ligand binding , nuclear translocation and consequently , gene regulation . this view is supported by the observation that treating cells with the hsp90 inhibitor geldanamycin can effectively suppress gr ligand binding and transcriptional activity 
					 [ tago et al . , however , the critical issue as to whether the hsp90-gr functional interaction is regulated and what mechanisms are involved has not yet been addressed .   our recent characterization of hsp90 acetylation may have provided an answer to this important question . in a search for proteins that associate with the microtubule - associated cytoplasmic deacetylase hdac6 
					 [ hubbert et al . , inactivation of hdac6 leads to the accumulation of acetylated hsp90 , which is accompanied by a failure of hsp90 to form a stable complex with gr , or with the critical co - chaperone p23 . this results in gr that is defective in ligand binding , nuclear translocation and transcriptional activity . these findings provide experimental evidence that the hsp90-gr interaction and , consequently the structural maturation of gr are indeed subject to regulation by acetylation , and implicates hdac6-mediated deacetylation of molecular chaperones as a potential novel mechanism that impinges on steroid hormone signaling 
					 [ kovacs et al . , for a number of years hsp90 has been perceived as a stress - induced protein with a more general housekeeping function .   a very different picture , however , has recently started to emerge . hsp90 and its co - factors , termed co - chaperones , form molecular chaperone complexes that facilitate the structural maturation of its substrates , termed client proteins . the hsp90-assisted maturation of client proteins often leads to an enhanced activity and stability for these client proteins 
					 [ pratt and toft , 2003 ] 
				 . the characterization of hsp90 client proteins led to a surprising realization that , instead of proteins with housekeeping functions , many hsp90 client proteins are critical for cell signaling , including oncogenic kinases such as erbb2 akt , raf and bcr - abl and the aforementioned glucocorticoid receptor 
					 [ pratt , 1997 ] 
				 . supporting the importance of hsp90 in cell signaling , hsp90 inhibitors , such as geldanamycin , display potent biological effects , and can induce growth arrest and apoptosis in tumor cell lines 
					 [ blagosklonny et al . , the emerging significance of hsp90 in both normal and oncogenic signaling highlights the need to understand how hsp90 is regulated , the characterization of the hdac6-hsp90 interaction now identifies acetylation as one potential regulatory mechanism for hsp90 activity . traditionally post - translational modification by acetylation has been linked to histone and chromatin - dependent processes . recent evidence , however , strongly suggests that reversible acetylation can regulate important biological processes independent of chromatin 
					 [ cohen and yao , 2004 ] 
				 . for example , the characterization of hdac6 has implicated protein acetylation in the regulation of microtubule dynamics , growth factor - induced chemotaxis and the processing of misfolded protein aggregates 
					 [ hubbert et al . , 2002 ; 
					 haggarty et al . , consistent with these apparently non - genomic functions , hdac6 is mainly localized to the cytoplasm where it dynamically associates with cytoskeleton . accordingly , identifying substrates for hdac6 would be critical to decipher how hdacs might regulate non - chromatin related processes .   in a search for such targets , we identified hsp90 as a substrate for hdac6 
					 [ kovacs et al . , although it remains unclear whether hsp90 also serves as a critical mediator for the established functions of hdac6 in cell motility and aggresome formation , acetylation of hsp90 , induced by inhibiting hdac6 via specific sirna or through the use of an inhibitor trichostatin a ( tsa ) , clearly reduces gr activity . this is particularly interesting as recent reports also found that tsa treatment inhibits glucocorticoid - mediated transcriptional activity 
					 [ ito et al . , this inhibition is , however , unexpected as tsa treatment often activates gene transcription nonspecifically by inducing histone hyperacetylation . our results help to reconcile these observations and point to an effect of tsa on cytoplasmic hdac6 rather than on histones or chromatin .   in the presence of tsa , hsp90 is unable to properly bind gr , thus affecting the ability of gr to illicit a transcriptional response . importantly , these findings also indicate that hsp90-mediated gr maturation is not simply a constitutive or housekeeping process ; rather , it can be regulated through hsp90 acetylation , providing another level of regulation in steroid hormone signaling . the relationship that we have characterized between reversible acetylation and gr signaling begs a series of interesting questions . one prevalent question is whether or not other steroid hormone receptors are subjected to the same regulation . evidence indicates that ar , er , and pr 
					 [ fang et al . , 1996 ; the hsp90 inhibitor geldanamycin ( ga ) has been reported to inhibit the activity of ar , gr , and pr 
					 [ solit et al . , 2002 ; 
					 tago et al . , 2004 ; if these receptors indeed require hsp90 for full activity , hdac6 might turn out to be an important modulator for more than just one steroid hormone receptor . similarly , given that several prominent hsp90 client proteins are intimately linked to human cancer 
					 [ neckers and neckers , 2005 ] 
				 , it would be of great interest to investigate whether hsp90 acetylation is also important for the maturation and activity of these oncoproteins .   the answer to these questions not only would determine whether hsp90 acetylation plays a more general role in regulating chaperone activity toward a broad spectrum of client proteins , but also point to a potential cancer therapeutic approach through the suppression of hsp90 deacetylation . although the exact nature of this ligand - induced acetylation remains to be characterized , it is tantalizing to speculate that acetylation might be coupled with the maturation of gr . for example , hsp90 acetylation might allow the conversion of gr - hsp90 from a stable complex into a dynamic one by dissociating p23 from the hsp90 complex , thereby enabling gr to enter the nucleus for transcriptional activation . as acetylated hsp90 appears to have reduced binding toward gr and p23 , the subsequent deacetylation by hdac6 would then allow hsp90 to re - enter the productive chaperone complex ( figure 1 ) . interestingly , it appears that certain cellular stresses , such as those associated with the transformation from normal to oncogenic state , can also cause hsp90 chaperone complex remodeling 
					 [ kamal et al . , we speculate that acetylation of molecular chaperones might play a role in the dynamic reorganization of chaperone complexes in response to such  oncogenic stress  . we suspect that oncogenic stress , which might be induced by high demand for  growth and proliferation-associated signaling , may lead to a spike in the levels of acetylated hsp90 due to an increase in hsp90-client proteins during robust cellular growth .   under this scenario , hdac6 may then be required for robust hsp90 activity by regenerating deacetylated hsp90 and thereby ensuring effective cell signaling . this model would also argue that hdac6 might play a more important role for cells under specific stress conditions , such as oncogenic transformation induced by hsp90 client proteins . steroid hormone receptors are critical for normal development and homeostasis . over - expression or misregulation of receptors and their signaling pathways , however , can lead to a myriad of disease states . for example , aberrant glucocorticoid levels have been associated with muscle atrophy including disuse atrophy and cachexia , a disorder characterized by muscle wasting and malnutrition 
					 [ hasselgren , 1999 ] 
				 .   indeed , increased levels of gr signaling can induce muscle atrophy , possibly through activation of foxo transcription factors and the atrophy - related ubiquitin ligases mafbx and murf1 , which are involved in the increase of cellular proteolysis associated with muscle atrophy 
					 [ bodine et al . , 2001 ; 
					 glass , 2003 ] 
				 .   in the case of ar and er , it is well documented that mutations and over - expression of ar are associated with prostate cancer 
					 [ rahman et al . , 2004 ; 
					 suzuki et al . , 2003 ] 
				  while er has been intimately linked to both the progression and metastasis of breast cancer 
					 [ osborne and schiff , 2005 ] 
				 . if hsp90 acetylation plays an important role in gr , ar and/or er signaling , it is conceivable that pharmacological manipulation of hsp90 acetylation could represent a critical therapeutic strategy to abrogate aberrant steroid receptor signaling . the development of selective high affinity inhibitors similar to tubacin 
					 [ haggarty et al . , 2003 ] 
				  may allow for an attenuation of oncogenic signaling while allowing hsp90 to manage house keeping cellular activities . the dynamic hsp90 acetylation in glucocorticoid receptor function has revealed another level of regulation in steroid hormone signaling . recent evidence has come forth to suggest that acetylation of hsp90 effects atp binding 
					 [ murphy et al . , what is the identity of the chaperone acetyltransferase ( which we have dubbed chat ) ?   is hdac6 the only hsp90 deacetylase ? how is hsp90 acetylation regulated by selective cell signaling ?   is the entire population or only a selected pool of hsp90 subject to the regulation by reversible acetylation ? are there other components of the chaperone complex regulated by reversible acetylation ? by elucidating the functional relationship between acetylation and chaperone - mediated signaling in various cellular processes , we may go a long way towards understanding how we might use these mechanisms to our own advantage to battle everything from cancer to muscle atrophy . the dynamic hsp90 acetylation in glucocorticoid receptor function has revealed another level of regulation in steroid hormone signaling . recent evidence has come forth to suggest that acetylation of hsp90 effects atp binding 
					 [ murphy et al . , what is the identity of the chaperone acetyltransferase ( which we have dubbed chat ) ?   is hdac6 the only hsp90 deacetylase ?   how is hsp90 acetylation regulated by selective cell signaling ? is the entire population or only a selected pool of hsp90 subject to the regulation by reversible acetylation ? are there other components of the chaperone complex regulated by reversible acetylation ? by elucidating the functional relationship between acetylation and chaperone - mediated signaling in various cellular processes , we may go a long way towards understanding how we might use these mechanisms to our own advantage to battle everything from cancer to muscle atrophy . reversible acetylation may regulate the recycling of hsp90 in and out of functional chaperone complexes . the deacetylation of hsp90 allows for the recruitment and binding of co - chaperones such as p23 , and may allow for the recruitment of other co - chaperones ( y and z ) such as p50 , hop , immunophilins , etc ( 1 ) . the formation of this chaperone complex facilitates folding of gr that is competent for ligand binding ( red receptor ) , translocation into the nucleus and transcriptional activation . ligand binding destabilizes the gr - hsp90 chaperone complex interaction ( 2 ) and induces hsp90 acetylation by the induction or activation of the chaperone acetyltransferase ( chat ; ( 3 ) ) . the chat may also be activated in response to other cellular stresses or  oncogenic stress(3 ) . acetylated hsp90 , which has a reduced affinity for p23 and possibly for other co - chaperones ( 4 ) , may further destabilize the gr - hsp90 interaction , allowing for the nuclear translocation of gr and subsequent transcriptional activation ( 5 ) . note that binding of certain co - chaperones may be insensitive to the acetylation status of hsp90 ( z ) . acetylated hsp90 is then deacetylated by hdac6 ( 6 ) , regenerating hsp90 that is competent for co - chaperone(s ) complex assembly ( 7 ) , productive chaperone cycles , and associating with inactive gr ( pink ) exported from the nucleus ( 8) . inactivation of hdac6 by tsa , tubacin or specific sirna would inhibit the regeneration of deacetylated hsp90 required for gr or selected client protein maturation ( 9 ) .