Enhancement of Stress Resilience Through Histone Deacetylase 6–Mediated Regulation of Glucocorticoid Receptor Chaperone Dynamics

Abstract

Background Acetylation of Hsp90 regulates downstream hormone signaling via the glucocorticoid receptor (GR), but the role of this molecular mechanism in stress homeostasis remains poorly understood. We tested whether acetylation of Hsp90 in the brain predicts and modulates the behavioral sequelae of a mouse model of social stress. Methods Mice subjected to chronic social defeat stress (CSDS) were stratified into resilient and vulnerable subpopulations. HPA axis function was probed using a DEX/CRF test. Hsp90 acetylation, Hsp90-GR interactions and GR translocation were measured in the dorsal raphe nucleus (DRN). To manipulate Hsp90 acetylation, we pharmacologically inhibited Hdac6, a known deacetylase of Hsp90 or overexpressed a point-mutant that mimics the hyperacetylated state of Hsp90 at lysine K294 Results Lower acetylated Hsp90, higher GR-Hsp90 association and enhanced GR translocation were observed in DRN of vulnerable mice after CSDS. Administration of ACY-738, an Hdac6-selective inhibitor, led to Hsp90 hyperacetylation in brain and in neuronal culture. In cell-based assays, ACY-738 increased the relative association of Hsp90 with FKBP51 versus FKBP52 and inhibited hormone-induced GR translocation. This effect was replicated by overexpressing the acetylation-mimic point-mutant of Hsp90. In vivo, ACY-738 promoted resilience to CSDS and serotonin-selective viral overexpression of the acetylation-mimic mutant of Hsp90 in raphe neurons reproduced the behaviroral effect of ACY-738. Conclusions Hyperacetylation of Hsp90 is a predictor and causal molecular determinant of stress resilience in mice. Brain-penetrant Hdac6 inhibitors increase Hsp90 acetylation and modulate GR chaperone dynamics offering a promising strategy to curtail deleterious socioaffective effects of stress and glucocorticoids.

Glucocorticoid Receptor Function and Resilience: A Tale of Mice and Men

“…Previous studies have found that genetically identical mice that are exposed to this paradigm can be split into separate vulnerable and resilient categories based on the degree of social interaction with other mice following this paradigm (3). In line with the findings of the Yehuda et al (1) article, Jochems et al (2) found that the mice that were vulnerable to CSDS had enhanced GR association with the chaperone protein heat shock protein 90 (Hsp90) and increased translocation of GR to the nucleus in the serotonin neurons of the dorsal raphe (DR). They focused on this region of the brain since previous studies have found that it plays a prominent role in the response to CSDS in mice (4)(5)(6).…”

“…(1) and Jochems et al (2) in this issue, both studies find an association between glucocorticoid receptor (GR) regulation and the response to traumatic stress. The first finds this association in the development of PTSD in combat veterans and the second in the development of a PTSD-like state in mice following exposure to chronic social defeat stress (CSDS).…”

“…The Jochems et al (2) article employed a mouse model of CSDS to determine if there are differences in GR function in animals that respond very differently to 10 days of attacks by other mice. Previous studies have found that genetically identical mice that are exposed to this paradigm can be split into separate vulnerable and resilient categories based on the degree of social interaction with other mice following this paradigm (3).…”

Hsp90 as a therapeutic target in endocrinology: current evidence

“…172 Recent studies have found an association between GR regulation and the response to traumatic stress. 173,174 The HDAC6 inhibitor, ACY-738, was shown to increase Hsp90 acetylation in mice, promoting increased incorporation of the FKBP51 cochaperone into Hsp90-GR complexes and causing a suppression of GR function. This led to an enhanced adaptation to stress.…”

“…This led to an enhanced adaptation to stress. 174 Thus, through its modulating influences on Hsp90, HDAC6 has been confirmed as a viable therapeutic target for psychosocial stress and depression. The continuing evolution of Hsp90 inhibitory drugs and their relevance to specific diseases hold great promise of exciting developments in the future.…”