Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function

Abstract

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.

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

“…found that impaired insulin signalling together with hyperglycemia prevents the nuclear translocation of transcription factor spliced X‐box binding protein 1 (sXBP1), which resulted in maladaptive ER stress signalling in podocytes and worsened DKD. Concomitantly, the same team found that coagulation protease activated protein C (aPC) maintains ER homoeostasis via sXBP1 in podocytes . Specifically, they revealed that aPC can compensate for the absence of insulin receptor in podocytes in mice with experimental diabetes.…”

“…Specifically, they revealed that aPC can compensate for the absence of insulin receptor in podocytes in mice with experimental diabetes. This occurred by activation of the PI3K p85‐subunit‐dependent nuclear translocation of sXBP1, which prevented the maladaptive ER stress …”

Coagulation Signalling and Metabolic Disorders: Lessons Learned from Animal Models

“…62 Experimental studies over the last decade in multiple mouse models of chronic-diabetic and acute kidney injury models delineated multiple cell-specific intracellular mechanisms that mediate aPC-dependent cytoprotective effects. [65][66][67][68] We recently uncovered an insulinlike function of aPC in the regulation of adaptive unfolded protein response in insulin-sensitive specialized glomerular epithelial cells called podocytes. 67 Disruption of aPC or insulin signalling or both impair function of podocytes ultimately causing dysfunction of the glomerular filtration barrier and dNP.…”

“…[65][66][67][68] We recently uncovered an insulinlike function of aPC in the regulation of adaptive unfolded protein response in insulin-sensitive specialized glomerular epithelial cells called podocytes. 67 Disruption of aPC or insulin signalling or both impair function of podocytes ultimately causing dysfunction of the glomerular filtration barrier and dNP. 67,69 Mechanistically, insulin and aPC converge on a common spliced-X-box binding protein-1 (sXBP1) signalling pathway to maintain endoplasmic reticulum (ER) proteostasis.…”

Advances in Clinical and Basic Science of Coagulation: Illustrated abstracts of the 9th Chapel Hill Symposium on Hemostasis

“…This effect, which conveys protective aspects of ER‐signaling, is lost in insulin resistance, promoting diabetic nephropathy. Activated protein C (aPC) signaling (4) via protease activated receptors 1 and 3 (PAR1/3) restores sXBP1‐p85 dissociation (2) and sXBP1nuclear translocation (3), maintaining kidney function . In vivo, aPC restores ER‐function and protects mice lacking the insulin receptor from aggravated diabetic nephropathy.…”