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Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion
Nature Communications ( IF 16.6 ) Pub Date : 2021-07-30 , DOI: 10.1038/s41467-021-24810-5
Silvia Martinelli 1 , Elmira A Anderzhanova 2, 3 , Thomas Bajaj 2 , Svenja Wiechmann 4, 5, 6 , Frederik Dethloff 1, 7 , Katja Weckmann 1 , Daniel E Heinz 2, 3 , Tim Ebert 2 , Jakob Hartmann 8 , Thomas M Geiger 9 , Michael Döngi 10 , Kathrin Hafner 1 , Max L Pöhlmann 11 , Lee Jollans 1 , Alexandra Philipsen 12 , Susanne V Schmidt 13 , Ulrike Schmidt 14, 15, 16 , Giuseppina Maccarrone 1 , Valentin Stein 10 , Felix Hausch 9 , Christoph W Turck 1 , Mathias V Schmidt 11 , Anne-Kathrin Gellner 10, 12 , Bernhard Kuster 4, 5, 6, 17 , Nils C Gassen 1, 2
Affiliation  

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.



中文翻译:

压力引发的分泌自噬通过增强 MMP9 分泌促进细胞外 BDNF 成熟

压力反应是维持体内平衡的重要机制,它的破坏与几种精神疾病有关。在细胞水平上,压力会激活自噬等机制,通过蛋白质降解和再循环来调节体内平衡。分泌性自噬是最近描述的一种途径,其中自噬体与质膜而不是溶酶体融合。在这里,我们证明糖皮质激素介导的压力通过应激反应性共伴侣 FK506 结合蛋白 51 增强分泌自噬。我们将基质金属蛋白酶 9 (MMP9) 确定为响应压力而分泌的蛋白质之一。使用细胞分析和体内微透析,我们进一步发现压力增强的 MMP9 分泌增加了前脑源性神经营养因子 (proBDNF) 向其成熟形式 (mBDNF) 的裂解。BDNF 对成人突触可塑性至关重要,其通路与重度抑郁症和创伤后应激障碍有关。这些发现揭示了一种细胞压力适应机制,该机制具有为理解压力相关疾病的病理生理学开辟道路的潜力。

更新日期:2021-07-30
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