SKA2 enhances stress- related glucocorticoid receptor signaling through FKBP4-FKBP5 interactions in neurons

• 成果类型: Article
• 署名作者: Hartmann, Jakob; Klengel, Claudia; Dillmann, Larissa J.; Hisey, Erin E.; Hafner, Kathrin; Shukla, Rammohan; Estruch, Marina Soliva; Bajaj, Thomas; Ebert, Tim; Mabbott, Katharine G.; Rostin, Luise; Philipsen, Alexandra; Carlezon Jr, William A.; Gisabella, Barbara; Mccullumsmith, Robert E.; Vergis, John M.; Klengel, Torsten; Daskalakis, Nikolaos P.; Pantazopoulos, Harry; Gassen, Nils C.; Ressler, Kerry J.
• 署名单位: Harvard University; Harvard University Medical Affiliates; McLean Hospital; Max Planck Society; University of Wyoming; University of Bonn; University of Mississippi Medical Center; University of Mississippi; University System of Ohio; University of Toledo
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11532
• DOI: 10.1073/pnas.2417728121
• 发表日期: 2024-12-24
• 关键词: pituitary-adrenal axis; gene-expression; hpa axis; major depression; bipolar disorder; fkbp5; cortisol; brain; methylation; suicide

摘要

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, SKA2, 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 FK506bindingprotein 51 (FKBP5) from the complex. FKBP4 and FKBP5 are cochaperones known to regulate GR function in opposite directions. Notably in mice, SKA2 in Crh+ 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.