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Leif Groop

Leif Groop

Principal investigator

Leif Groop

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

Author

  • Katarzyna Malenczyk
  • Fatima Girach
  • Edit Szodorai
  • Petter Storm
  • Åsa Segerstolpe
  • Giuseppe Tortoriello
  • Robert Schnell
  • Jan Mulder
  • Roman A. Romanov
  • Erzsébet Borók
  • Fabiana Piscitelli
  • Vincenzo Di Marzo
  • Gábor Szabó
  • Rickard Sandberg
  • Stefan Kubicek
  • Gert Lubec
  • Tomas Hökfelt
  • Ludwig Wagner
  • Leif Groop
  • Tibor Harkany

Summary, in English

Ca2+-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 Ca2+-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.

Department/s

  • Genomics, Diabetes and Endocrinology
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2017-06-21

Language

English

Pages

1993-2176

Publication/Series

EMBO Journal

Volume

36

Issue

14

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Cell and Molecular Biology

Keywords

  • Ca signalling
  • Diabetes
  • Endocannabinoid
  • Exocytosis
  • β-cell

Status

Published

Research group

  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 0261-4189