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

被引：52

作者：

Malenczyk, Katarzyna ^{[1
,2
]}

Girach, Fatima ^{[1
]}

Szodorai, Edit ^{[1
]}

Storm, Petter ^{[3
]}

Segerstolpe, Asa ^{[4
]}

Tortoriello, Giuseppe ^{[2
,13
]}

Schnell, Robert ^{[5
]}

Mulder, Jan ^{[6
]}

Romanov, Roman A. ^{[1
,2
]}

Borok, Erzsebet ^{[7
]}

Piscitelli, Fabiana ^{[8
]}

Di Marzo, Vincenzo ^{[8
]}

Szabo, Gabor ^{[9
]}

Sandberg, Rickard ^{[4
]}

Kubicek, Stefan ^{[10
]}

Lubec, Gert ^{[11
,14
]}

Hokfelt, Tomas ^{[2
]}

Wagner, Ludwig ^{[12
]}

Groop, Leif ^{[3
]}

Harkany, Tibor ^{[1
,2
]}

机构：

[1] Med Univ Vienna, Ctr Brain Res, Dept Mol Neurosci, Vienna, Austria

[2] Karolinska Inst, Dept Neurosci, Stockholm, Sweden

[3] Skane Univ Hosp Malmo, Dept Clin Sci Diabet & Endocrinol CRC, Malmo, Sweden

[4] Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden

[5] Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden

[6] Karolinska Inst, Sci Life Lab, Solna, Sweden

[7] Med Univ Vienna, Dept Cognit Neurobiol, Ctr Brain Res, Vienna, Austria

[8] CNR, Ist Chim Biomol, Endocannabinoid Res Grp, Naples, Italy

[9] Hungarian Acad Sci, Inst Expt Med, Budapest, Hungary

[10] CeMM Res Ctr Mol Med, Vienna, Austria

[11] Univ Vienna, Dept Pharmaceut Chem, Vienna, Austria

[12] Gen Hosp Vienna, Univ Clin Internal Med 3, Vienna, Austria

[13] Life Technol, Glasgow, Lanark, Scotland

[14] Neuroprote Lab, Sci Pk,Ilkovicova 8, Bratislava, Slovakia

来源：

EMBO JOURNAL | 2017年 / 36卷 / 14期

基金：

瑞典研究理事会; 欧洲研究理事会;

关键词：

Ca2+ signalling; beta-cell; diabetes; endocannabinoid; exocytosis; INSULIN-SECRETION; CANNABINOID RECEPTORS; INDUCED APOPTOSIS; TRPV1; CHANNEL; ER STRESS; BINDING PROTEIN; GENE-EXPRESSION; ION CHANNELS; SECRETAGOGIN; CALCIUM;

D O I：

10.15252/embj.201695347

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 beta-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 beta-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 beta-cells.

引用

页码：2107 / 2125

页数：19

共 103 条

[1] Transient receptor potential vanilloid subfamily 1 expressed in pancreatic islet β cells modulates insulin secretion in rats [J].