Abstract
The stress response is an essential mechanism for maintaining homeostasis, and its disruption is implicated in several psychiatric disorders. On the cellular level, stress activates, among other mechanisms, autophagy that regulates homeostasis through protein degradation and recycling. Secretory autophagy is a recently described pathway in which autophagosomes fuse with the plasma membrane rather than with lysosomes. Here, we demonstrate that glucocorticoid-mediated stress enhances secretory autophagy via the stress-responsive co-chaperone FK506-binding protein 51. We identify the matrix metalloproteinase 9 (MMP9) as one of the proteins secreted in response to stress. Using cellular assays and in vivo microdialysis, we further find that stress-enhanced MMP9 secretion increases the cleavage of pro-brain-derived neurotrophic factor (proBDNF) to its mature form (mBDNF). BDNF is essential for adult synaptic plasticity and its pathway is associated with major depression and posttraumatic stress disorder. These findings unravel a cellular stress adaptation mechanism that bears the potential of opening avenues for the understanding of the pathophysiology of stress-related disorders.
Highlights
The stress response is an essential mechanism for maintaining homeostasis, and its disruption is implicated in several psychiatric disorders
Our results demonstrate that GC-mediated stress enhances secretory autophagy via the co-chaperone FKBP51, and that matrix metalloproteinase 9 (MMP9) is among the regulated proteins leading to an extracellular increase in cleavage of pro-brain-derived neurotrophic factor to its mature form both in vitro and in vivo
This release pathway comprises a stepwise succession of signaling proteins defined by three regulatory stages: (1) the disruption of lysosomal membranes by a stressor and the recruitment by galectins of a receptor, such as TRIM16, and its cargo; (2) the transport of the receptor-cargo complex to the autophagosomal membrane via the R-SNARE SEC22B; (3) the internalization of the cargo protein into the autophagosome followed by its fusion with the plasma membrane that is mediated by the complex formation of R- and Q-SNARE proteins (RQ-SNARE complex)
Summary
The stress response is an essential mechanism for maintaining homeostasis, and its disruption is implicated in several psychiatric disorders. BDNF is essential for adult synaptic plasticity and its pathway is associated with major depression and posttraumatic stress disorder These findings unravel a cellular stress adaptation mechanism that bears the potential of opening avenues for the understanding of the pathophysiology of stress-related disorders. Impairment of proteostatic regulation in the brain contributes to the development of proteinopathies and excessive inflammatory responses, hallmarks of neurodegenerative and neuropsychiatric diseases[7,8,9] Cellular stressors such as starvation, oxidative stress, and infection are known threats to proteostasis, counteracted by autophagy. Our results demonstrate that GC-mediated stress enhances secretory autophagy via the co-chaperone FKBP51, and that matrix metalloproteinase 9 (MMP9) is among the regulated proteins leading to an extracellular increase in cleavage of pro-brain-derived neurotrophic factor (proBDNF) to its mature form (mBDNF) both in vitro and in vivo. We unveil a mechanism linking autophagy, as GCmediated stress response, to neuroplasticity—key features intimately connected to stress adaptation and stress-related disorders
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