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

Malenczyk, Katarzyna; Girach, Fatima; Szodorai, Edit; Storm, Petter LU ; Segerstolpe, Åsa; Tortoriello, Giuseppe; Schnell, Robert; Mulder, Jan; Romanov, Roman A. and Borók, Erzsébet, et al. (2017) In EMBO Journal 36(13).
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... (More)

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.

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publication status
epub
subject
keywords
Ca signalling, Diabetes, Endocannabinoid, Exocytosis, β-cell
in
EMBO Journal
volume
36
issue
13
publisher
Oxford University Press
external identifiers
  • scopus:85021324243
  • wos:000405478400010
ISSN
0261-4189
DOI
10.15252/embj.201695347
language
English
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yes
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61832d71-ce27-47ca-90bf-cd6413a507cf
date added to LUP
2017-07-13 12:15:55
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2017-09-18 11:38:20
@article{61832d71-ce27-47ca-90bf-cd6413a507cf,
  abstract     = {<p>Ca<sup>2+</sup>-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<sup>2+</sup>-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(<sup>-/-</sup>) mice. However, instead of merely impinging on the SNARE machinery, reduced insulin availability in secretagogin<sup>-/-</sup> 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.</p>},
  author       = {Malenczyk, Katarzyna and Girach, Fatima and Szodorai, Edit and Storm, Petter and Segerstolpe, Åsa and Tortoriello, Giuseppe and Schnell, Robert and Mulder, Jan and Romanov, Roman A. and Borók, Erzsébet and Piscitelli, Fabiana and Di Marzo, Vincenzo and Szabó, Gábor and Sandberg, Rickard and Kubicek, Stefan and Lubec, Gert and Hökfelt, Tomas and Wagner, Ludwig and Groop, Leif and Harkany, Tibor},
  issn         = {0261-4189},
  keyword      = {Ca signalling,Diabetes,Endocannabinoid,Exocytosis,β-cell},
  language     = {eng},
  month        = {06},
  number       = {13},
  publisher    = {Oxford University Press},
  series       = {EMBO Journal},
  title        = {A TRPV1-to-secretagogin regulatory axis controls pancreatic β-cell survival by modulating protein turnover},
  url          = {http://dx.doi.org/10.15252/embj.201695347},
  volume       = {36},
  year         = {2017},
}