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Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity

Molecular Psychiatry volume 27, pages 2533–2545 (2022)Cite this article

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Abstract

FKBP51 is an important inhibitor of the glucocorticoid receptor (GR) signaling. High FKBP51 levels are associated to stress-related disorders, which are linked to GR resistance. SUMO conjugation to FKBP51 is necessary for FKBP51’s inhibitory action on GR. The GR/FKBP51 pathway is target of antidepressant action. Thus we investigated if these drugs could inhibit FKBP51 SUMOylation and therefore restore GR activity. Screening cells using Ni2+ affinity and in vitro SUMOylation assays revealed that tricyclic antidepressants- particularly clomipramine- inhibited FKBP51 SUMOylation. Our data show that clomipramine binds to FKBP51 inhibiting its interaction with PIAS4 and therefore hindering its SUMOylation. The inhibition of FKBP51 SUMOylation decreased its binding to Hsp90 and GR facilitating FKBP52 recruitment, and enhancing GR activity. Reduction of PIAS4 expression in rat primary astrocytes impaired FKBP51 interaction with GR, while clomipramine could no longer exert its inhibitory action. This mechanism was verified in vivo in mice treated with clomipramine. These results describe the action of antidepressants as repressors of FKBP51 SUMOylation as a molecular switch for restoring GR sensitivity, thereby providing new potential routes of antidepressant intervention.

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Fig. 1: Tricyclic antidepressants inhibit FKBP51 SUMO conjugation.
Fig. 2: Tricyclic antidepressants inhibit PIAS4 activity and interaction with FKBP51.
Fig. 3: Clomipramine effect is restricted to FKBP51 SUMO conjugation.
Fig. 4: Clomipramine restores FKBP51 cochaperone activity.
Fig. 5: Clomipramine inhibition is mediated by regulation of PIAS4 activity on FKBP51.
Fig. 6: Proposed model: SUMOylated FKBP51 interacts with Hsp90 and GR, decreases GR ligand binding and its nuclear translocation, leading to the inhibition of GR activity.

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References

  1. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338:171–9.

    Article  CAS  PubMed  Google Scholar 

  2. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology. 2000;23:477–501.

    Article  CAS  PubMed  Google Scholar 

  3. Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci. 2006;8:383–95.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Keller-Wood M. Hypothalamic-pituitary-adrenal axis-feedback control. Compr Physiol. 2015;5:1161–82.

    Article  PubMed  Google Scholar 

  5. de Kloet ER, Joels M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6:463–75.

    Article  PubMed  CAS  Google Scholar 

  6. Groeneweg FL, Karst H, de Kloet ER, Joels M. Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling. Mol Cell Endocrinol. 2012;350:299–309.

    Article  CAS  PubMed  Google Scholar 

  7. Pariante CM, Miller AH. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol Psychiatry. 2001;49:391–404.

    Article  CAS  PubMed  Google Scholar 

  8. Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34:S186–95.

    Article  CAS  PubMed  Google Scholar 

  9. Dedovic K, Ngiam J. The cortisol awakening response and major depression: examining the evidence. Neuropsychiatr Dis Treat. 2015;11:1181–9.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Menke A. Is the HPA axis as target for depression outdated, or is there a new hope? Front Psychiatry. 2019;10:101.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Anacker C, Zunszain PA, Carvalho LA, Pariante CM. The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology. 2011;36:415–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Seckl JR, Fink G. Antidepressants increase glucocorticoid and mineralocorticoid receptor mRNA expression in rat hippocampus in vivo. Neuroendocrinology. 1992;55:621–6.

    Article  CAS  PubMed  Google Scholar 

  13. Przegalinski E, Budziszewska B. The effect of long-term treatment with antidepressant drugs on the hippocampal mineralocorticoid and glucocorticoid receptors in rats. Neurosci Lett. 1993;161:215–8.

    Article  CAS  PubMed  Google Scholar 

  14. Reul JM, Stec I, Soder M, Holsboer F. Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system. Endocrinology. 1993;133:312–20.

    Article  CAS  PubMed  Google Scholar 

  15. Montkowski A, Barden N, Wotjak C, Stec I, Ganster J, Meaney M, et al. Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function. J Neuroendocrinol. 1995;7:841–5.

    Article  CAS  PubMed  Google Scholar 

  16. Pepin MC, Govindan MV, Barden N. Increased glucocorticoid receptor gene promoter activity after antidepressant treatment. Mol Pharmacol. 1992;41:1016–22.

    CAS  PubMed  Google Scholar 

  17. Herr AS, Tsolakidou AF, Yassouridis A, Holsboer F, Rein T. Antidepressants differentially influence the transcriptional activity of the glucocorticoid receptor in vitro. Neuroendocrinology. 2003;78:12–22.

    Article  CAS  PubMed  Google Scholar 

  18. Guidotti G, Calabrese F, Anacker C, Racagni G, Pariante CM, Riva MA. Glucocorticoid receptor and FKBP5 expression is altered following exposure to chronic stress: modulation by antidepressant treatment. Neuropsychopharmacology. 2013;38:616–27.

    Article  CAS  PubMed  Google Scholar 

  19. Wei K, Xu Y, Zhao Z, Wu X, Du Y, Sun J, et al. Icariin alters the expression of glucocorticoid receptor, FKBP5 and SGK1 in rat brains following exposure to chronic mild stress. Int J Mol Med. 2016;38:337–44.

    Article  CAS  PubMed  Google Scholar 

  20. Storer CL, Dickey CA, Galigniana MD, Rein T, Cox MB. FKBP51 and FKBP52 in signaling and disease. Trends Endocrinol Metab. 2011;22:481–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Grad I, Picard D. The glucocorticoid responses are shaped by molecular chaperones. Mol Cell Endocrinol. 2007;275:2–12.

    Article  CAS  PubMed  Google Scholar 

  22. Wochnik GM, Ruegg J, Abel GA, Schmidt U, Holsboer F, Rein T. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J Biol Chem. 2005;280:4609–16.

    Article  CAS  PubMed  Google Scholar 

  23. Jääskeläinen T, Makkonen H, Palvimo JJ. Steroid up-regulation of FKBP51 and its role in hormone signaling. Curr Opin Pharmacol. 2011;11:326–31.

    Article  PubMed  CAS  Google Scholar 

  24. Denny WB, Valentine DL, Reynolds PD, Smith DF, Scammell JG. Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology. 2000;141:4107–13.

    Article  CAS  PubMed  Google Scholar 

  25. Tatro ET, Everall IP, Kaul M, Achim CL. Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52: implications for major depressive disorder. Brain Res. 2009;1286:1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kino T. Stress, glucocorticoid hormones, and hippocampal neural progenitor cells: implications to mood disorders. Front Physiol. 2015;6:230.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Boyle MP, Brewer JA, Funatsu M, Wozniak DF, Tsien JZ, Izumi Y, et al. Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior. Proc Natl Acad Sci USA. 2005;102:473–8.

    Article  CAS  PubMed  Google Scholar 

  28. Scharf SH, Liebl C, Binder EB, Schmidt MV, Muller MB. Expression and regulation of the Fkbp5 gene in the adult mouse brain. PLoS ONE. 2011;6:e16883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet. 2004;36:1319–25.

    Article  CAS  PubMed  Google Scholar 

  30. Ising M, Maccarrone G, Bruckl T, Scheuer S, Hennings J, Holsboer F, et al. FKBP5 gene expression predicts antidepressant treatment outcome in depression. Int J Mol Sci. 2019;20.

  31. Fabbri C, Hosak L, Mossner R, Giegling I, Mandelli L, Bellivier F, et al. Consensus paper of the WFSBP Task Force on Genetics: genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response. World J Biol Psychiatry. 2017;18:5–28.

    Article  PubMed  Google Scholar 

  32. Wang Q, Shelton RC, Dwivedi Y. Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: a systematic review and meta-analysis. J Affect Disord. 2018;225:422–8.

    Article  CAS  PubMed  Google Scholar 

  33. Zimmermann P, Bruckl T, Nocon A, Pfister H, Binder EB, Uhr M, et al. Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: results from a 10-year prospective community study. Am J Psychiatry. 2011;168:1107–16.

    Article  PubMed  Google Scholar 

  34. Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299:1291–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ising M, Depping AM, Siebertz A, Lucae S, Unschuld PG, Kloiber S, et al. Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls. Eur J Neurosci. 2008;28:389–98.

    Article  PubMed  Google Scholar 

  36. Gassen NC, Fries GR, Zannas AS, Hartmann J, Zschocke J, Hafner K, et al. Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine. Sci Signal. 2015;8:ra119.

    Article  PubMed  CAS  Google Scholar 

  37. Gassen NC, Hartmann J, Zschocke J, Stepan J, Hafner K, Zellner A, et al. Association of FKBP51 with priming of autophagy pathways and mediation of antidepressant treatment response: evidence in cells, mice, and humans. PLoS Med. 2014;11:e1001755.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hartmann J, Wagner KV, Liebl C, Scharf SH, Wang XD, Wolf M, et al. The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress. Neuropharmacology. 2012;62:332–9.

    Article  CAS  PubMed  Google Scholar 

  39. O’Leary JC 3rd, Dharia S, Blair LJ, Brady S, Johnson AG, Peters M, et al. A new anti-depressive strategy for the elderly: ablation of FKBP5/FKBP51. PLoS ONE. 2011;6:e24840.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Touma C, Gassen NC, Herrmann L, Cheung-Flynn J, Bull DR, Ionescu IA, et al. FK506 binding protein 5 shapes stress responsiveness: modulation of neuroendocrine reactivity and coping behavior. Biol Psychiatry. 2011;70:928–36.

    Article  CAS  PubMed  Google Scholar 

  41. Hartmann J, Wagner KV, Gaali S, Kirschner A, Kozany C, Ruhter G, et al. Pharmacological inhibition of the psychiatric risk factor FKBP51 has anxiolytic properties. J Neurosci. 2015;35:9007–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Geiss-Friedlander R, Melchior F. Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol. 2007;8:947–56.

    Article  CAS  PubMed  Google Scholar 

  43. Antunica-Noguerol M, Budzinski ML, Druker J, Gassen NC, Sokn MC, Senin S, et al. The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51. Cell Death Differ. 2016;23:1579–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Karst H, Karten YJ, Reichardt HM, de Kloet ER, Schutz G, Joels M. Corticosteroid actions in hippocampus require DNA binding of glucocorticoid receptor homodimers. Nat Neurosci. 2000;3:977–8.

    Article  CAS  PubMed  Google Scholar 

  45. Conrad CD. Chronic stress-induced hippocampal vulnerability: the glucocorticoid vulnerability hypothesis. Rev Neurosci. 2008;19:395–411.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Gassen NC, Hartmann J, Zannas AS, Kretzschmar A, Zschocke J, Maccarrone G, et al. FKBP51 inhibits GSK3beta and augments the effects of distinct psychotropic medications. Mol Psychiatry. 2016;21:277–89.

    Article  CAS  PubMed  Google Scholar 

  47. Matosin N, Halldorsdottir T, Binder EB. Understanding the molecular mechanisms underpinning gene by environment interactions in psychiatric disorders: the FKBP5 model. Biol Psychiatry. 2018;83:821–30.

    Article  CAS  PubMed  Google Scholar 

  48. Funato H, Kobayashi A, Watanabe Y. Differential effects of antidepressants on dexamethasone-induced nuclear translocation and expression of glucocorticoid receptor. Brain Res. 2006;1117:125–34.

    Article  CAS  PubMed  Google Scholar 

  49. Mukherjee K, Knisely A, Jacobson L. Partial glucocorticoid agonist-like effects of imipramine on hypothalamic-pituitary-adrenocortical activity, thymus weight, and hippocampal glucocorticoid receptors in male C57BL/6 mice. Endocrinology. 2004;145:4185–91.

    Article  CAS  PubMed  Google Scholar 

  50. Okugawa G, Omori K, Suzukawa J, Fujiseki Y, Kinoshita T, Inagaki C. Long-term treatment with antidepressants increases glucocorticoid receptor binding and gene expression in cultured rat hippocampal neurones. J Neuroendocrinol. 1999;11:887–95.

    Article  CAS  PubMed  Google Scholar 

  51. Owens MJ, Morgan WN, Plott SJ, Nemeroff CB. Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther. 1997;283:1305–22.

    CAS  PubMed  Google Scholar 

  52. Gassen NC, Rein T. Is there a role of autophagy in depression and antidepressant action? Front Psychiatry. 2019;10:337.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Hisaoka-Nakashima K, Kajitani N, Kaneko M, Shigetou T, Kasai M, Matsumoto C, et al. Amitriptyline induces brain-derived neurotrophic factor (BDNF) mRNA expression through ERK-dependent modulation of multiple BDNF mRNA variants in primary cultured rat cortical astrocytes and microglia. Brain Res. 2016;1634:57–67.

    Article  CAS  PubMed  Google Scholar 

  54. Rossi M, Rotblat B, Ansell K, Amelio I, Caraglia M, Misso G, et al. High throughput screening for inhibitors of the HECT ubiquitin E3 ligase ITCH identifies antidepressant drugs as regulators of autophagy. Cell Death Dis. 2014;5:e1203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Jaffray EG, Hay RT. Detection of modification by ubiquitin-like proteins. Methods. 2006;38:35–8.

    Article  CAS  PubMed  Google Scholar 

  56. Chun TH, Itoh H, Subramanian L, Iniguez-Lluhi JA, Nakao K. Modification of GATA-2 transcriptional activity in endothelial cells by the SUMO E3 ligase PIASy. Circ Res. 2003;92:1201–8.

    Article  CAS  PubMed  Google Scholar 

  57. Hollenberg SM, Evans RM. Multiple and cooperative trans-activation domains of the human glucocorticoid receptor. Cell. 1988;55:899–906.

    Article  CAS  PubMed  Google Scholar 

  58. Lee H, Quinn JC, Prasanth KV, Swiss VA, Economides KD, Camacho MM, et al. PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein. Genes Dev. 2006;20:784–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rathmell WK, Hickey MM, Bezman NA, Chmielecki CA, Carraway NC, Simon MC. In vitro and in vivo models analyzing von Hippel-Lindau disease-specific mutations. Cancer Res. 2004;64:8595–603.

    Article  CAS  PubMed  Google Scholar 

  60. Jha S, Gupta A, Dar A, Dutta A. RVBs are required for assembling a functional TIP60 complex. Mol Cell Biol. 2013;33:1164–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P, et al. Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol. 1997;17:5946–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Inda C, Dos Santos Claro PA, Bonfiglio JJ, Senin SA, Maccarrone G, Turck CW, et al. Different cAMP sources are critically involved in G protein-coupled receptor CRHR1 signaling. J Cell Biol. 2016;214:181–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Perisic T, Zimmermann N, Kirmeier T, Asmus M, Tuorto F, Uhr M, et al. Valproate and amitriptyline exert common and divergent influences on global and gene promoter-specific chromatin modifications in rat primary astrocytes. Neuropsychopharmacology. 2010;35:792–805.

    Article  CAS  PubMed  Google Scholar 

  64. Zschocke J, Zimmermann N, Berning B, Ganal V, Holsboer F, Rein T. Antidepressant drugs diversely affect autophagy pathways in astrocytes and neurons-dissociation from cholesterol homeostasis. Neuropsychopharmacology. 2011;36:1754–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Cai Q, Verma SC, Kumar P, Ma M, Robertson ES. Hypoxia inactivates the VHL tumor suppressor through PIASy-mediated SUMO modification. PLoS ONE. 2010;5:e9720.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Naidu SR, Lakhter AJ, Androphy EJ. PIASy-mediated Tip60 sumoylation regulates p53-induced autophagy. Cell Cycle. 2012;11:2717–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Risso G, Pelisch F, Pozzi B, Mammi P, Blaustein M, Colman-Lerner A, et al. Modification of Akt by SUMO conjugation regulates alternative splicing and cell cycle. Cell Cycle. 2013;12:3165–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cheung-Flynn J, Roberts PJ, Riggs DL, Smith DF. C-terminal sequences outside the tetratricopeptide repeat domain of FKBP51 and FKBP52 cause differential binding to Hsp90. J Biol Chem. 2003;278:17388–94.

    Article  CAS  PubMed  Google Scholar 

  69. Fukuda I, Ito A, Hirai G, Nishimura S, Kawasaki H, Saitoh H, et al. Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate. Chem Biol. 2009;16:133–40.

    Article  CAS  PubMed  Google Scholar 

  70. Schulke JP, Wochnik GM, Lang-Rollin I, Gassen NC, Knapp RT, Berning B, et al. Differential impact of tetratricopeptide repeat proteins on the steroid hormone receptors. PLoS ONE. 2010;5:e11717.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Davies TH, Ning YM, Sanchez ER. A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. J Biol Chem. 2002;277:4597–600.

    Article  CAS  PubMed  Google Scholar 

  72. Riggs DL, Roberts PJ, Chirillo SC, Cheung-Flynn J, Prapapanich V, Ratajczak T, et al. The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo. EMBO J. 2003;22:1158–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Paakinaho V, Kaikkonen S, Makkonen H, Benes V, Palvimo JJ. SUMOylation regulates the chromatin occupancy and anti-proliferative gene programs of glucocorticoid receptor. Nucleic Acids Res. 2014;42:1575–92.

    Article  CAS  PubMed  Google Scholar 

  74. Paakinaho V, Lempiäinen JK, Sigismondo G, Niskanen EA, Malinen M, Jääskeläinen T, et al. SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites. Nucleic Acids Res. 2021;49:1951–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Drouin J, Trifiro MA, Plante RK, Nemer M, Eriksson P, Wrange O. Glucocorticoid receptor binding to a specific DNA sequence is required for hormone-dependent repression of pro-opiomelanocortin gene transcription. Mol Cell Biol. 1989;9:5305–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Carter BS, Meng F, Thompson RC. Glucocorticoid treatment of astrocytes results in temporally dynamic transcriptome regulation and astrocyte-enriched mRNA changes in vitro. Physiol Genomics. 2012;44:1188–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Li H, Su P, Lai TK, Jiang A, Liu J, Zhai D, et al. The glucocorticoid receptor-FKBP51 complex contributes to fear conditioning and posttraumatic stress disorder. J Clin Investig. 2020;130:877–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sayad A, Taheri M, Azari I, Oskoei VK, Ghafouri-Fard S. PIAS genes as disease markers in bipolar disorder. J Cell Biochem. 2019;120:12937–42.

    Article  CAS  PubMed  Google Scholar 

  79. Tertil M, Skupio U, Barut J, Dubovyk V, Wawrzczak-Bargiela A, Soltys Z, et al. Glucocorticoid receptor signaling in astrocytes is required for aversive memory formation. Transl Psychiatry. 2018;8:255.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Peppi M, Kujawa SG, Sewell WF. A corticosteroid-responsive transcription factor, promyelocytic leukemia zinc finger protein, mediates protection of the cochlea from acoustic trauma. J Neurosci. 2011;31:735–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Spijker S, Van Zanten JS, De Jong S, Penninx BW, van Dyck R, Zitman FG, et al. Stimulated gene expression profiles as a blood marker of major depressive disorder. Biol Psychiatry. 2010;68:179–86.

    Article  CAS  PubMed  Google Scholar 

  82. Zannas AS, Jia M, Hafner K, Baumert J, Wiechmann T, Pape JC, et al. Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappaB-driven inflammation and cardiovascular risk. Proc Natl Acad Sci USA. 2019;116:11370–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr. Alejandro Leroux for the technical help in the thermal shift assay. This work was supported by grants from the Max Planck Society, Germany; University of Buenos Aires; CONICET; Agencia Nacional de Promoción Científica y Tecnológica, Argentina; and FOCEM-Mercosur (COF 03/11); “OptiMD” grant of the Federal Ministry of Education and Research Germany (01EE1401D; MVS).

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  1. These authors contributed equally: Maia L. Budziñski, Clara Sokn.

Authors and Affiliations

  1. Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, C1425FQD, Argentina

    Maia L. Budziñski, Clara Sokn, Romina Gobbini, Belén Ugo, María Antunica-Noguerol, Sergio Senin, Eduardo Arzt & Ana C. Liberman

  2. Neurohomeostasis Research Group, Department of Psychiatry, Bonn Clinical Center, University of Bonn, 53127, Bonn, Germany

    Thomas Bajaj & Nils C. Gassen

  3. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, D-80804, Munich, Germany

    Nils C. Gassen, Theo Rein & Elisabeth B. Binder

  4. Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, D-80804, Munich, Germany

    Mathias V. Schmidt

  5. Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, C1428EGA, Argentina

    Eduardo Arzt

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Contributions

NCG, MLB, TR, MVS, EA, and ACL designed the experiments; MLB, CS, RG, BU, NCG, and TB performed the experiments; MVS, NCG, TB, and MLB performed the in vivo experiments with mice; SS assisted technically; MLB, TR, EA, and ACL analyzed the data; MLB and ACL collated the data and wrote the manuscript; ACL, TR, NCG, MVS, EA, and EBB discussed and corrected the manuscript. All authors contributed to the manuscript.

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Budziñski, M.L., Sokn, C., Gobbini, R. et al. Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity. Mol Psychiatry 27, 2533–2545 (2022). https://doi.org/10.1038/s41380-022-01491-0

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