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Article

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

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, View ORCID ProfileTibor Harkany
DOI 10.15252/embj.201695347 | Published online 21.06.2017
The EMBO Journal (2017) e201695347
Katarzyna Malenczyk
Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, AustriaDepartment of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Fatima Girach
Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria
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Edit Szodorai
Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria
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Petter Storm
Department of Clinical Sciences, Diabetes and Endocrinology CRC, Skåne University Hospital Malmö, Malmö, Sweden
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Åsa Segerstolpe
Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden
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Giuseppe Tortoriello
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Robert Schnell
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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Jan Mulder
Science for Life Laboratory, Karolinska Institutet, Solna, Sweden
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Roman A Romanov
Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, AustriaDepartment of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Erzsébet Borók
Department of Cognitive Neurobiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
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Fabiana Piscitelli
Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli Naples, Italy
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Vincenzo Di Marzo
Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli Naples, Italy
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Gábor Szabó
Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
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Rickard Sandberg
Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden
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Stefan Kubicek
CeMM Research Centre for Molecular Medicine, Vienna, Austria
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Gert Lubec
Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
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Tomas Hökfelt
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Ludwig Wagner
University Clinic for Internal Medicine III, General Hospital Vienna, Vienna, Austria
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Leif Groop
Department of Clinical Sciences, Diabetes and Endocrinology CRC, Skåne University Hospital Malmö, Malmö, Sweden
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Tibor Harkany
Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, AustriaDepartment of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Author Affiliations

  1. Katarzyna Malenczyk1,2,
  2. Fatima Girach1,
  3. Edit Szodorai1,
  4. Petter Storm3,
  5. Åsa Segerstolpe4,
  6. Giuseppe Tortoriello2,13,
  7. Robert Schnell5,
  8. Jan Mulder6,
  9. Roman A Romanov1,2,
  10. Erzsébet Borók7,
  11. Fabiana Piscitelli8,
  12. Vincenzo Di Marzo8,
  13. Gábor Szabó9,
  14. Rickard Sandberg4,
  15. Stefan Kubicek10,
  16. Gert Lubec11,14,
  17. Tomas Hökfelt2,
  18. Ludwig Wagner12,
  19. Leif Groop3 and
  20. Tibor Harkany (tibor.harkany{at}meduniwien.ac.at)*,1,2
  1. 1Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria
  2. 2Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
  3. 3Department of Clinical Sciences, Diabetes and Endocrinology CRC, Skåne University Hospital Malmö, Malmö, Sweden
  4. 4Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden
  5. 5Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  6. 6Science for Life Laboratory, Karolinska Institutet, Solna, Sweden
  7. 7Department of Cognitive Neurobiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
  8. 8Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli Naples, Italy
  9. 9Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
  10. 10CeMM Research Centre for Molecular Medicine, Vienna, Austria
  11. 11Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
  12. 12University Clinic for Internal Medicine III, General Hospital Vienna, Vienna, Austria
  13. 13Present Address: Life Technologies, Glasgow, UK
  14. 14Present Address: Neuroproteomics Laboratory Science Park, Ilkovicova 8, Bratislava, Slovakia
  1. ↵*Corresponding author. Tel: +43 1 40160 34050; Fax: +43 1 40160 934053; E‐mail: tibor.harkany{at}meduniwien.ac.at
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Abstract

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.

Synopsis

Embedded Image

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.

  • Ca2+ entry through TRP family channels regulates secretagogin transcription in β‐cells via the Ca2+‐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.

  • Ca2+‐bound secretagogin interacts with USP9X and USP7 to regulate β‐cell turnover. Pharmacological modulation of protein degradation rescues β‐cell viability.

  • Ca2+ signalling
  • β‐cell
  • diabetes
  • endocannabinoid
  • exocytosis
  • Received July 27, 2016.
  • Revision received April 27, 2017.
  • Accepted May 9, 2017.
  • © 2017 The Authors
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Volume 37, Issue 8
13 April 2018 | pp -
The EMBO Journal: 37 (8)
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