TY - JOUR
T1 - SKA2 enhances stress-related glucocorticoid receptor signaling through FKBP4–FKBP5 interactions in neurons
AU - Hartmann, Jakob
AU - Klengel, Claudia
AU - Dillmann, Larissa J.
AU - Hisey, Erin E.
AU - Hafner, Kathrin
AU - Shukla, Rammohan
AU - Estruch, Marina Soliva
AU - Bajaj, Thomas
AU - Ebert, Tim
AU - Mabbott, Katharine G.
AU - Rostin, Luise
AU - Philipsen, Alexandra
AU - Carlezon, William A.
AU - Gisabella, Barbara
AU - McCullumsmith, Robert E.
AU - Vergis, John M.
AU - Klengel, Torsten
AU - Berretta, Sabina
AU - Daskalakis, Nikolaos P.
AU - Pantazopoulos, Harry
AU - Gassen, Nils C.
AU - Ressler, Kerry J.
N1 - Publisher Copyright:
© 2024 the Author(s).
PY - 2024/12/24
Y1 - 2024/12/24
N2 - 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 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 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.
AB - 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 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 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.
KW - bipolar disorder
KW - glucocorticoid receptor
KW - hippocampus
KW - HPA axis
KW - stress
UR - http://www.scopus.com/inward/record.url?scp=85213224402&partnerID=8YFLogxK
U2 - 10.1073/pnas.2417728121
DO - 10.1073/pnas.2417728121
M3 - Article
C2 - 39705315
AN - SCOPUS:85213224402
SN - 0027-8424
VL - 121
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 52
M1 - e2417728121
ER -