Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, Bonn Clinical Center, University of Bonn, Bonn, Germany.
Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany.
Autophagy. 2022 Nov;18(11):2756-2758. doi: 10.1080/15548627.2022.2063006. Epub 2022 Apr 19.
Stress and changes in energy stores are perceived by hormone- and nutrient-sensing nuclei of the hypothalamus, which orchestrate an adaptive physiological body response to maintain homeostasis. Macroautophagy/autophagy is a fundamental lysosomal degradation system contributing to preservation of proteome balance and metabolic homeostasis. Its dysregulation is linked to diverse human pathologies, including neuropsychiatric and metabolic disorders. Autophagy is coordinated by cellular nutrient sensors, including AMPK and MTORC1 that interact with WIPI proteins. Studies suggest that WDR45/WIPI4 interacts with the stress-sensitive co-chaperone FKBP5/FKBP51, which has emerged as a key autophagy scaffold. However, the impact of FKBP5 on autophagy signaling in response to metabolic challenges, such as a high-fat diet, is elusive. Therefore, we manipulated FKBP5 in the mediobasal hypothalamus (MBH) and studied autophagy signaling and protein interactions in their physiological context. We identified FKBP5 as a scaffold of the STK11/LKB1-AMPK complex with WDR45/WIPI4 and TSC2 with WDR45B/WIPI3 in response to metabolic challenges, positioning FKBP5 in major nutrient-sensing and autophagy-regulating networks. Intriguingly, we could demonstrate that deletion in the MBH strongly induces obesity, whereas its overexpression protects against high-fat diet-induced obesity. Our findings suggest a crucial regulatory and adaptive function of FKBP5-regulated autophagy within the MBH in response to metabolic challenges.: AKT: thymoma viral proto-oncogene; AMPK: AMP-activated protein kinase; BECN1: beclin 1, autophagy related; eWAT: epididymal white adipose tissue; FKBP5/FKBP51: FK506 binding protein 5; KO, knockout; MBH, mediobasal hypothalamus; MTORC1, mechanistic target of rapamycin kinase complex 1; p: phosphorylated; PHLPP: PH domain and leucine rich repeat protein phosphatase; RPS6KB/p70S6K: ribosomal protein S6 kinase; SKP2: S-phase kinase-associated protein 2; SM: soleus muscle; SQSTM1/p62, sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TSC: TSC complex; ULK1: unc-51 like kinase 1; WIPI: WD repeat domain, phosphoinositide interacting; WT: wild type.
应激和能量储存的变化被下丘脑的激素和营养感应核感知，这些核协调适应性生理反应以维持体内平衡。巨自噬/自噬是一种基本的溶酶体降解系统，有助于维持蛋白质组平衡和代谢平衡。其失调与多种人类疾病有关，包括神经精神和代谢紊乱。自噬受细胞营养传感器的协调，包括 AMPK 和 MTORC1，它们与 WIPI 蛋白相互作用。研究表明，WDR45/WIPI4 与应激敏感伴侣 FKBP5/FKBP51 相互作用，后者已成为关键的自噬支架。然而，FKBP5 对代谢应激（如高脂肪饮食）下自噬信号的影响尚不清楚。因此，我们在中脑基底部（MBH）中操纵 FKBP5，并在生理环境中研究自噬信号和蛋白质相互作用。我们发现 FKBP5 是 STK11/LKB1-AMPK 复合物的支架，与 WDR45/WIPI4 和 TSC2 与 WDR45B/WIPI3 相互作用，以响应代谢挑战，将 FKBP5 定位于主要的营养感应和自噬调节网络中。有趣的是，我们可以证明 MBH 中的缺失强烈诱导肥胖，而其过表达可防止高脂肪饮食诱导的肥胖。我们的研究结果表明，FKBP5 调节的自噬在 MBH 中对代谢挑战的反应中具有关键的调节和适应性功能。：AKT：胸腺瘤病毒原癌基因；AMPK：AMP 激活的蛋白激酶；BECN1：自噬相关蛋白 beclin 1；eWAT：附睾白色脂肪组织；FKBP5/FKBP51：FK506 结合蛋白 5；KO，敲除；MBH，中脑基底部；MTORC1，雷帕霉素靶蛋白激酶复合物 1；p：磷酸化；PHLPP：PH 域和富含亮氨酸重复蛋白磷酸酶；RPS6KB/p70S6K：核糖体蛋白 S6 激酶；SKP2：S 期激酶相关蛋白 2；SM：比目鱼肌；SQSTM1/p62，自噬相关蛋白 1；STK11/LKB1：丝氨酸/苏氨酸激酶 11；TSC：TSC 复合物；ULK1：UNC-51 样激酶 1；WIPI：WD 重复域，磷酸肌醇相互作用；WT：野生型。
