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A TRPV 1‐to‐secretagogin regulatory axis controls pancreatic β‐cell survival by modulating protein turnover
Author(s) -
Malenczyk Katarzyna,
Girach Fatima,
Szodorai Edit,
Storm Petter,
Segerstolpe Åsa,
Tortoriello Giuseppe,
Schnell Robert,
Mulder Jan,
Romanov Roman A,
Borók Erzsébet,
Piscitelli Fabiana,
Di Marzo Vincenzo,
Szabó Gábor,
Sandberg Rickard,
Kubicek Stefan,
Lubec Gert,
Hökfelt Tomas,
Wagner Ludwig,
Groop Leif,
Harkany Tibor
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201695347
Subject(s) - biology , protein turnover , trpv , microbiology and biotechnology , biochemistry , receptor , protein biosynthesis , transient receptor potential channel , trpv1
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 ( TRPV 1) as potent inducers of secretagogin expression through recruitment of Sp1 transcription factors. Accordingly, agonist stimulation of TRPV 1s 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 USP 9X deubiquitinase activity. Therefore, and considering the desensitization of TRPV 1s in diabetic pancreata, a TRPV 1‐to‐secretagogin regulatory axis seems critical to maintain the structural integrity and signal competence of β‐cells.