Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function.
Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function.
复制标题
DOI：
10.1182/blood-2017-02-767921
复制
发表时间：
2017-09-21
期刊：
影响因子：
20.3
通讯作者：
Isermann B
中科院分区：
文献类型：
--
作者：
Madhusudhan T;Wang H;Ghosh S;Dong W;Kumar V;Al-Dabet MM;Manoharan J;Nazir S;Elwakiel A;Bock F;Kohli S;Marquardt A;Sögüt I;Shahzad K;Müller AJ;Esmon CT;Nawroth PP;Reiser J;Chavakis T;Ruf W;Isermann B
凝血蛋白酶在止血和血栓形成之外具有越来越多的公认功能。活化蛋白C（aPC）或胰岛素信号传导的破坏都损害足细胞的功能，并最终导致肾小球滤过屏障功能障碍和糖尿病肾病（DKD）。我们在这里表明，胰岛素和aPC会聚在一个共同的剪接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，生理水平的aPC维持DKD中内质网（ER）蛋白质稳态。因此，遗传受损的蛋白C活化加剧了适应不良的ER应答，而aPC的遗传或药理学恢复维持了DKD模型中的ER蛋白稳态。重要的是，在具有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下游信号传导中间体、PI3激酶的调节亚基、p85α和p85β来选择性地恢复细胞保护性ER转录因子sXBP1的活性。条件特异性XBP1转录调控模式的全基因组定位证实，一致的UPR靶基因参与胰岛素和aPC对ER蛋白质稳态的维持。因此，aPC有效地利用脱离的胰岛素信号传导组分来重新配置ER信号传导并恢复蛋白质稳态。这些结果将ER重编程鉴定为凝血蛋白酶的一种新的类胰岛素样功能，并证明靶向胰岛素信号传导中间体可能是改善缺陷胰岛素信号传导的可行治疗方法。
Coagulation proteases have increasingly recognized functions beyond hemostasis and thrombosis. Disruption of activated protein C (aPC) or insulin signaling both 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 endoplasmic reticulum (ER) proteostasis in DKD. Accordingly, genetically impaired protein C activation exacerbates maladaptive ER-response, while 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 UPR target genes are involved in maintenance of ER-proteostasis by both insulin and aPC. Thus, aPC efficiently employs disengaged insulin signaling components to re-configure ER-signaling and restore proteostasis. These results identify ER-reprogramming as a novel hormone-like function of coagulation proteases and demonstrate that targeting insulin signaling intermediates may be a feasible therapeutic approach ameliorating defective insulin signaling.
登录
查看更多内容
DOI：
10.1016/j.bbrc.2016.10.106
发表时间：
2016-11-25
影响因子：
3.1
作者：
Nam, Dae-Hwan;Han, Jung-Hwa;Woo, Chang-Hoon
通讯作者：
Woo, Chang-Hoon
影响因子：
48
作者：
Pepke, Shirley;Wold, Barbara;Mortazavi, Ali
通讯作者：
Mortazavi, Ali
DOI：
10.1083/jcb.201003138
发表时间：
2010-05-31
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rutkowski DT;Hegde RS
通讯作者：
Hegde RS
影响因子：
56.9
作者：
Hetz, C;Bernasconi, P;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
16
作者：
Acosta-Alvear, Diego;Zhou, Yiming;Dynlacht, Brian David
通讯作者：
Dynlacht, Brian David