Fig. 7: Proposed model based on the findings.

a Glucocorticoid-mediated stress induces lysosomal damage, which leads to the association of FKBP51 with the cargo receptor TRIM16 and the cargo protein (e.g., MMP9). This complex is transported on the autophagosome membrane via the interaction of FKBP51 with SEC22B. The cargo protein is internalized into the autophagosome which is transported to the plasma membrane. The vesicle-plasma membrane fusion is mediated via the SNARE-protein complex assembly, which is regulated by FKBP51 and sensitive to glucocorticoids. The membrane fusion leads to the release of the cargo proteins into the extracellular milieu. The increased secretion of extracellular MMP9 induces the cleavage of proBDNF to its mature form, which becomes the prevailing form in the extracellular space; b A first response to stress triggers lytic autophagy¹⁰. In case the stress persists, a second defense line is activated which switches the stress response from lytic to secretory autophagy. If stress further persists (e.g. chronic stress), the initially beneficial proteins secreted in response to stress, might lead to neuroinflammation and psychiatric disorders.