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DOI: 10.1055/s-0033-1353271
The Hsp90 cochaperone FKBP51 impacts autophagy and protein kinases relevant to psychiatric diseases
While FKBP51 is firmly established as a potent inhibitor of the glucocorticoid receptor (GR) and crucial factor in stress-related psychiatric diseases, we here set out to identify novel molecular networks beyond FKBP51's action on GR and to test the relevance of these networks for the actions of antidepressants. We investigated the influence of FKBP51 on protein kinases including Akt; Akt is a key regulator of the PI3K/Akt/mTOR pathway. We report a specific interaction of FKBP51 and its close homologue FKBP52 with Akt1 and 2. FKBP51 recruited the phosphatases PHLPP1 and 2 to Akt1 and 2 leading to dephosphorylation of the latter and thus inactivation of downstream signalling as assessed by phosphorylation of Foxo3a. FKBP51 also affected targets downstream of the Akt pathway, as exemplified for its impact on autophagy: Analysis of LC3B distribution revealed that ectopically expressed FKBP51 induced redistribution of LC3 into autophagosomal vesicles in rat cortical astrocytes. Furthermore, the levels of beclin1 and LC3B-II were increased. Virtually all of these FKBP51 actions were shared by antidepressants; importantly, the effects of antidepressants were greatly enhanced by increasing FKBP51. Altogether, we put forward the hypothesis that FKBP51 is a crucial determinant of antidepressants' action on Akt/mTOR signaling and downstream physiological processes such as autophagy, thereby evidencing a role of autophagy in psychiatric diseases.