A TRPV1-to-secretagogin regulatory axis controls pancreatic ß-cell survival by modulating protein turnover.
EMBO J
; 36(14): 2107-2125, 2017 07 14.
Article
in En
| MEDLINE
| ID: mdl-28637794
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 ß-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 ß-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 ß-cells.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Proteins
/
Gene Expression Regulation
/
Insulin-Secreting Cells
/
TRPV Cation Channels
/
Secretagogins
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
EMBO J
Year:
2017
Type:
Article
Affiliation country:
Austria