Madhusudhan Thati, Wang Hongjie, Ghosh Sanchita, Dong Wei, Kumar Varun, Al-Dabet Moh'd Mohanad, Manoharan Jayakumar, Nazir Sumra, Elwakiel Ahmed, Bock Fabian, Kohli Shrey, Marquardt Andi, Sögüt Ibrahim, Shahzad Khurrum, Müller Andreas J, Esmon Charles T, Nawroth Peter P, Reiser Jochen, Chavakis Triantafyllos, Ruf Wolfram, Isermann Berend
Institute of Clinical Chemistry and Pathobiochemistry, Otto von Guericke University Magdeburg, Magdeburg, Germany.
Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.
Blood. 2017 Sep 21;130(12):1445-1455. doi: 10.1182/blood-2017-02-767921. Epub 2017 Jul 7.
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.
凝血蛋白酶的功能已越来越多地被认识到超出了止血和血栓形成的范畴。活化蛋白C(aPC)或胰岛素信号通路的破坏会损害足细胞的功能,并最终导致肾小球滤过屏障功能障碍和糖尿病肾病(DKD)。我们在此表明,胰岛素和aPC汇聚于一条共同的剪接X盒结合蛋白1(sXBP1)信号通路,以维持内质网(ER)的稳态。与胰岛素类似,aPC的生理水平可维持DKD中的内质网蛋白质稳态。因此,遗传性蛋白C激活受损会加剧适应性内质网反应,而aPC的基因或药理学恢复可在DKD模型中维持内质网蛋白质稳态。重要的是,在足细胞特异性胰岛素受体(INSR)缺陷的小鼠中,aPC通过暂时靶向INSR下游信号中间体(PI3激酶的调节亚基p85α和p85β)来选择性地恢复细胞保护性内质网转录因子sXBP1的活性。全基因组范围内条件特异性XBP1转录调控模式的图谱证实,一致的未折叠蛋白反应靶基因参与了胰岛素和aPC对内质网蛋白质稳态的维持。因此,aPC有效地利用分离的胰岛素信号成分来重新配置内质网信号并恢复蛋白质稳态。这些结果将内质网重编程确定为凝血蛋白酶的一种新型激素样功能,并表明靶向胰岛素信号中间体可能是改善胰岛素信号缺陷的一种可行治疗方法。