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

Thati Madhusudhan, Hongjie Wang, Sanchita Ghosh, Wei Dong, Varun Kumar, Moh'd Mohanad Al-Dabet, Jayakumar Manoharan, Sumra Nazir, Ahmed Elwakiel, Fabian Bock, Shrey Kohli, Andi Marquardt, Ibrahim Sögüt, Khurrum Shahzad, Andreas J. Müller, Charles T. Esmon, Peter P. Nawroth, Jochen Reiser, Triantafyllos Chavakis, Wolfram Ruf and Berend Isermann

Key points

  • The coagulation protease aPC compensates for defective insulin signaling through ER-reprogramming.

  • PI3Kinase p85α, p85β and the ER-transcription factor XBP1 mechanistically link aPC signaling to ER-homeostasis in diabetic nephropathy.

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.

  • Submitted February 13, 2017.
  • Accepted June 27, 2017.