A depression-associated protein FKBP5 functions in autophagy initiation through scaffolding the VPS34 complex

Common variants in the FKBP5 gene have been implicated in recurrence of major depressive disorder (MDD) and response to antidepressant treatment. Although the relationship between FKBP5 and MDD has been revealed through several studies, the detailed molecular mechanisms by which FKBP5 regulates responsiveness to antidepressants have not been fully understood. Here, we aimed to elucidate the molecular mechanisms of FKBP5 in autophagy initiation and its potential role in the antidepressant response. We found that FKBP5 deficiency impaired the initiation of basal and stress-induced autophagy, accompanied by reduced protein levels of the PIK3C3/VPS34 complex, which is essential for autophagy initiation. Mechanistically, we demonstrated that FKBP5 physically binds to the VPS34 complex components, facilitating their assembly and subsequent autophagy initiation. Particularly, our study revealed that FKBP5 mediates antidepressant-induced autophagy by promoting the VPS34 complex assembly. These findings were consistent in neuronal cells, where FKBP5 depletion resulted in decreased autophagy and impaired the VPS34 complex assembly. Understanding the interplay between FKBP5, autophagy, and MDD may provide new insights into more effective treatments for MDD and related disorders.