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Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function
Blood ( IF 20.3 ) Pub Date : 2017-09-21 , DOI: 10.1182/blood-2017-02-767921
Thati Madhusudhan 1, 2 , Hongjie Wang 1, 3 , Sanchita Ghosh 1 , Wei Dong 1, 4 , Varun Kumar 5 , Moh'd Mohanad Al-Dabet 1 , Jayakumar Manoharan 1 , Sumra Nazir 1 , Ahmed Elwakiel 1 , Fabian Bock 1, 6 , Shrey Kohli 1 , Andi Marquardt 1 , Ibrahim Sögüt 1, 7 , Khurrum Shahzad 1, 8 , Andreas J. Müller 9, 10 , Charles T. Esmon 11, 12 , Peter P. Nawroth 5 , Jochen Reiser 13 , Triantafyllos Chavakis 14 , Wolfram Ruf 2, 15 , Berend Isermann 1
Affiliation  

Coagulation proteases have increasingly recognized functions beyond hemostasis and thrombosis. Disruption of activated protein C (aPC) or insulin signaling impair function of podocytes and ultimately cause dysfunction of the glomerular filtration barrier and diabetic kidney disease (DKD). We here show that insulin and aPC converge on a common spliced-X-box binding protein-1 (sXBP1) signaling pathway to maintain endoplasmic reticulum (ER) homeostasis. Analogous to insulin, physiological levels of aPC maintain ER proteostasis in DKD. Accordingly, genetically impaired protein C activation exacerbates maladaptive ER response, whereas genetic or pharmacological restoration of aPC maintains ER proteostasis in DKD models. Importantly, in mice with podocyte-specific deficiency of insulin receptor (INSR), aPC selectively restores the activity of the cytoprotective ER-transcription factor sXBP1 by temporally targeting INSR downstream signaling intermediates, the regulatory subunits of PI3Kinase, p85α and p85β. Genome-wide mapping of condition-specific XBP1-transcriptional regulatory patterns confirmed that concordant unfolded protein response target genes are involved in maintenance of ER proteostasis by both insulin and aPC. Thus, aPC efficiently employs disengaged insulin signaling components to reconfigure ER signaling and restore proteostasis. These results identify ER reprogramming as a novel hormonelike function of coagulation proteases and demonstrate that targeting insulin signaling intermediates may be a feasible therapeutic approach ameliorating defective insulin signaling.



中文翻译:

PI3K-p85-XBP1集线器上的信号整合赋予了凝固蛋白酶活化的蛋白C胰岛素样功能

凝血蛋白酶已被越来越多地认识到止血和血栓形成以外的功能。活化蛋白C(aPC)的破坏或胰岛素信号传导破坏足细胞的功能,并最终导致肾小球滤过屏障功能障碍和糖尿病肾病(DKD)。我们在这里显示,胰岛素和aPC会在共同的剪接X盒结合蛋白1(sXBP1)信号传导途径上收敛,以维持内质网(ER)稳态。与胰岛素类似,aPC的生理水平可维持DKD中的ER蛋白变性。因此,基因受损的蛋白C激活加剧了适应不良的ER反应,而aPC的遗传或药理学恢复可维持DKD模型中的ER蛋白水解。重要的是,在足细胞特异性胰岛素受体(INSR)缺乏的小鼠中,aPC通过暂时靶向INSR下游信号传导中间体,PI3Kinase,p85α和p85β的调节亚基,选择性地恢复细胞保护性ER转录因子sXBP1的活性。全基因组条件特异的XBP1转录调控模式的映射证实,一致的未折叠的蛋白质反应靶基因参与了胰岛素和aPC维持ER变形的过程。因此,aPC有效地利用了脱离的胰岛素信号传导成分来重新配置ER信号传导并恢复了蛋白稳态。这些结果确定ER重编程为凝血蛋白酶的新型激素样功能,并证明靶向胰岛素信号传导中间体可能是减轻缺陷胰岛素信号传导的可行治疗方法。

更新日期:2017-09-21
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