A TRPV1‐to‐secretagogin regulatory axis controls pancreatic β‐cell survival by modulating protein turnover

Ca 2+ ‐sensor proteins are generally implicated in insulin release through SNARE interactions. Here, secretagogin, whose expression in human pancreatic islets correlates with their insulin content and the incidence of type 2 diabetes, is shown to orchestrate an unexpectedly distinct mechanism. Single‐cell RNA‐seq reveals retained expression of the TRP family members in β‐cells from diabetic donors. Amongst these, pharmacological probing identifies Ca 2+ ‐permeable transient receptor potential vanilloid type 1 channels (TRPV1) as potent inducers of secretagogin expression through recruitment of Sp1 transcription factors. Accordingly, agonist stimulation of TRPV1s fails to rescue insulin release from pancreatic islets of glucose intolerant secretagogin knock‐out( −/− ) mice. However, instead of merely impinging on the SNARE machinery, reduced insulin availability in secretagogin −/− mice is due to β‐cell loss, which is underpinned by the collapse of protein folding and deregulation of secretagogin‐dependent USP9X deubiquitinase activity. Therefore, and considering the desensitization of TRPV1s in diabetic pancreata, a TRPV1‐to‐secretagogin regulatory axis seems critical to maintain the structural integrity and signal competence of β‐cells. Synopsis TRPV1 activates Sp1‐mediated secretagogin transcription in pancreatic β‐cells to regulate β‐cell survival, ER stress and glucose tolerance. Single‐cell RNA‐seq maps the expression of TRP family members to pancreatic β‐cells. Ca 2+ entry through TRP family channels regulates secretagogin transcription in β‐cells via the Ca 2+ ‐dependent transcription factor Sp1. Secretagogin knock‐out mice are insensitive to the pharmacological activation of TRPV1 receptors. Secretagogin knock‐out mice are glucose intolerant and suffer from endoplasmic reticulum stress due to the breakdown of protein chaperone availability. In healthy and type 2 diabetic human β‐cells secretagogin mRNA expression correlates with those of insulin, ATF4 and CHOP. Ca 2+ ‐bound secretagogin interacts with USP9X and USP7 to regulate β‐cell turnover. Pharmacological modulation of protein degradation rescues β‐cell viability. Graphical Abstract Calcium channel‐dependent induction of the calcium sensor secretagogin regulates insulin secretion not merely via the SNARE machinery, but also through the interacting deubiquitinase USP9X preventing ER stress and β‐cell loss.