Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity
Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity
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DOI：
10.1038/s41380-022-01491-0
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发表时间：
2022-03-08
影响因子：
11
通讯作者：
Liberman, Ana C.
中科院分区：
文献类型：
--
作者：
Budzinski, Maia L.;Sokn, Clara;Liberman, Ana C.
FKBP 51是糖皮质激素受体（GR）信号传导的重要抑制剂。高FKBP 51水平与应激相关疾病有关，这些疾病与GR抗性有关。FKBP 51抑制GR的作用需要SUMO与FKBP 51结合。GR/FKBP 51通路是抗抑郁作用的靶点。因此，我们研究了这些药物是否可以抑制FKBP 51 SUMO化，从而恢复GR活性。使用Ni 2+亲和性和体外SUMO化测定筛选细胞显示，三环类抗抑郁药-特别是氯丙咪嗪-抑制FKBP 51 SUMO化。我们的数据显示氯丙咪嗪与FKBP 51结合，抑制其与PIAS 4的相互作用，从而阻碍其SUMO化。FKBP 51 SUMO化的抑制降低了其与Hsp 90和GR的结合，促进FKBP 52募集，并增强GR活性。PIAS 4在大鼠原代星形胶质细胞中表达的减少损害了FKBP 51与GR的相互作用，而氯丙咪嗪不再发挥其抑制作用。在用氯丙咪嗪治疗的小鼠体内验证了该机制。这些结果描述了抗抑郁药作为FKBP 51 SUMO化的阻遏物作为恢复GR敏感性的分子开关的作用，从而提供了新的潜在的抗抑郁药干预途径。
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.