Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity

被引：14

作者：

Budzinski, Maia L. ^{[1
]}

Sokn, Clara ^{[1
]}

Gobbini, Romina ^{[1
]}

Ugo, Belen ^{[1
]}

Antunica-Noguerol, Maria ^{[1
]}

Senin, Sergio ^{[1
]}

Bajaj, Thomas ^{[2
]}

Gassen, Nils C. ^{[2
,3
]}

Rein, Theo ^{[3
]}

Schmidt, Mathias, V ^{[4
]}

Binder, Elisabeth B. ^{[3
]}

Arzt, Eduardo ^{[1
,5
]}

Liberman, Ana C. ^{[1
]}

机构：

[1] Inst Invest Biomed Buenos Aires IBioBA, Partner Inst Max Planck Soc, CONICET, C1425FQD, Buenos Aires, DF, Argentina

[2] Univ Bonn, Bonn Clin Ctr, Dept Psychiat, Neurohomeostasis Res Grp, D-53127 Bonn, Germany

[3] Max Planck Inst Psychiat, Dept Translat Res Psychiat, D-80804 Munich, Germany

[4] Max Planck Inst Psychiat, Res Grp Neurobiol Stress Resilience, D-80804 Munich, Germany

[5] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Fisiol & Biol Mol & Celular, C1428EGA, Buenos Aires, DF, Argentina

来源：

MOLECULAR PSYCHIATRY | 2022年 / 27卷 / 05期

关键词：

POSTTRAUMATIC-STRESS-DISORDER; MAJOR DEPRESSIVE DISORDER; MESSENGER-RNA EXPRESSION; LONG-TERM TREATMENT; GENE-EXPRESSION; TRANSCRIPTIONAL ACTIVITY; NUCLEAR TRANSLOCATION; SUMO CONJUGATION; AXIS REGULATION; UP-REGULATION;

D O I：

10.1038/s41380-022-01491-0

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2533 / 2545

页数：13

共 82 条

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