SKA2 enhances stress-related glucocorticoid receptor signaling through FKBP4–FKBP5 interactions in neurons
Genes involved in regulating the hypothalamic-pituitary-adrenal (HPA) axis, including the glucocorticoid receptor (GR), are linked to various stress-related psychopathologies including bipolar disorder as well as other mood and trauma-related disorders. The protein product of the cell cycle gene, <i>SKA2,</i> is a GR interaction partner in peripheral cells. However, the precise roles of SKA2 in stress and GR signaling in the brain, specifically in nonreplicating postmitotic neurons, and its involvement in HPA axis regulation remain unclear. Here, we demonstrate, using diverse in vitro cell assays, a mechanism by which SKA2 promotes GR signaling through enhancing GR-FKBP4 interaction leading to dissociation of FK506-bindingprotein 51 (FKBP5) from the complex. FKBP4 and FKBP5 are cochaperones known to regulate GR function in opposite directions. Notably in mice, SKA2 in <i>Crh</i><sup>+</sup> neurons of the paraventricular nucleus of the hypothalamus is crucial for HPA axis responsiveness and for maintaining the negative feedback loop underlying allostasis. Moreover, we show that SKA2 expression is increased in postmortem human hippocampus and amygdala from individuals with BD. Our study highlights a critical role of SKA2 in HPA axis function, adds to the understanding of the molecular basis of stress-related psychiatric disorders, and points to potential targets for intervention.
Authors
- Jakob Hartmann (ORCID: https://orcid.org/0000-0002-1960-8177)
- Erin Hisey (ORCID: https://orcid.org/0000-0001-6517-2522)
- Rammohan Shukla (ORCID: https://orcid.org/0000-0001-5776-2506)
- Sabina Berretta (ORCID: https://orcid.org/0000-0002-4057-7766)
- Thomas Bajaj (ORCID: https://orcid.org/0000-0001-6153-6608)
- William A. Carlezon (ORCID: https://orcid.org/0000-0002-4162-3947)
- Nils C. Gassen (ORCID: https://orcid.org/0000-0002-4265-3398)
- Torsten Klengel (ORCID: https://orcid.org/0000-0001-7045-9229)
- Tim Ebert
- Robert E. McCullumsmith (ORCID: https://orcid.org/0000-0001-6921-7150)
- Larissa J. Dillmann (ORCID: https://orcid.org/0000-0003-2014-8419)
- Claudia Klengel
- Alexandra Philipsen (ORCID: https://orcid.org/0000-0001-6876-518X)
- Kerry James Ressler (ORCID: https://orcid.org/0000-0002-5158-1103)
- Barbara Gisabella (ORCID: https://orcid.org/0000-0002-0072-790X)
- Nikolaos P. Daskalakis (ORCID: https://orcid.org/0000-0003-1660-9112)
- Harry Pantazopoulos (ORCID: https://orcid.org/0000-0002-8905-8377)
- John Vergis (ORCID: https://orcid.org/0009-0006-0864-3264)
- Luise Rostin
- Kathrin Hafner
- Marina Soliva Estruch
- Katharine G. Mabbott
Institutions
- University of Wyoming (US)
- Harvard University (US)
- University Hospital Bonn (DE)
- McLean Hospital (US)
- University of Mississippi Medical Center (US)
- Max Planck Institute of Psychiatry (DE)
- University of Toledo (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-12-20
- DOI
- https://doi.org/10.1073/pnas.2417728121
- Citations
- 12
- Primary Topic
- Stress Responses and Cortisol
- Type
- article
- Field-Weighted Citation Impact
- 3.51
Funders
- McLean Hospital
- University of Wyoming
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Institute of Mental Health