The F-actin modifier villin regulates insulin granule dynamics and exocytosis downstream of islet cell autoantigen 512.
The F-actin modifier villin regulates insulin granule dynamics and exocytosis downstream of islet cell autoantigen 512.
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DOI：
10.1016/j.molmet.2016.05.015
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发表时间：
2016-08
影响因子：
8.1
通讯作者：
Solimena M
中科院分区：
文献类型：
--
作者：
Mziaut H;Mulligan B;Hoboth P;Otto O;Ivanova A;Herbig M;Schumann D;Hildebrandt T;Dehghany J;Sönmez A;Münster C;Meyer-Hermann M;Guck J;Kalaidzidis Y;Solimena M
应严格控制胰岛β细胞的胰岛素释放，以避免低血糖和胰岛素抵抗。皮质肌动蛋白细胞骨架通过限制胰岛素分泌颗粒（SGs）的流动性和进入质膜来调节其胞外分泌。先前的研究表明，SGs通过其跨膜货物胰岛细胞自身抗原512 (Ica512)（也称为胰岛抗原2/Ptprn）与F-actin相互作用。在这里，我们研究了Ica512如何调节SG运输和胞吐。分析Ica512−/−小鼠胰岛的转录组学变化。成像以及生物物理和生化方法被用来验证ica512调节基因绒毛蛋白是否以及如何调节小鼠胰岛和胰岛素瘤细胞的胰岛素分泌。在Ica512- / -小鼠胰岛和Ica512-缺失的胰岛素瘤细胞中，f -肌动蛋白修饰因子绒毛蛋白持续下调。β细胞的细胞皮层富集绒毛蛋白，分散的绒毛蛋白- / -胰岛细胞不太圆，不太变形。绒毛蛋白缺失细胞中SGs的基础迁移率增强。此外，在缺乏绒毛蛋白或Ica512 f -肌动蛋白抑制皮质SGs的细胞中，基底分泌增加，而葡萄糖刺激的胰岛素释放减弱。后一种变化通过在ica512缺失的细胞中过表达绒毛蛋白而恢复，反之则不然。我们的研究结果表明，绒毛蛋白控制了限制SGs的f -肌动蛋白笼的大小，从而调节了它们的动力学和胞吐的可用性。绒毛蛋白作用于Ica512下游的证据也表明，SGs直接影响皮质肌动蛋白细胞骨架的重塑特性，从而严格控制胰岛素分泌。ica512缺失降低了f -肌动蛋白修饰物绒毛蛋白的遗传表达。绒毛蛋白耗竭增强基础胰岛素颗粒的流动性和胞吐。绒毛蛋白调节抑制胰岛素颗粒的肌动蛋白笼的大小。绒毛蛋白作用于胰岛素颗粒货物Ica512的下游。ica512 -绒毛蛋白基因链使颗粒能够控制细胞骨架的可塑性。
Insulin release from pancreatic islet β cells should be tightly controlled to avoid hypoglycemia and insulin resistance. The cortical actin cytoskeleton is a gate for regulated exocytosis of insulin secretory granules (SGs) by restricting their mobility and access to the plasma membrane. Prior studies suggest that SGs interact with F-actin through their transmembrane cargo islet cell autoantigen 512 (Ica512) (also known as islet antigen 2/Ptprn). Here we investigated how Ica512 modulates SG trafficking and exocytosis. Transcriptomic changes in Ica512−/− mouse islets were analyzed. Imaging as well as biophysical and biochemical methods were used to validate if and how the Ica512-regulated gene villin modulates insulin secretion in mouse islets and insulinoma cells. The F-actin modifier villin was consistently downregulated in Ica512−/− mouse islets and in Ica512-depleted insulinoma cells. Villin was enriched at the cell cortex of β cells and dispersed villin−/− islet cells were less round and less deformable. Basal mobility of SGs in villin-depleted cells was enhanced. Moreover, in cells depleted either of villin or Ica512 F-actin cages restraining cortical SGs were enlarged, basal secretion was increased while glucose-stimulated insulin release was blunted. The latter changes were reverted by overexpressing villin in Ica512-depleted cells, but not vice versa. Our findings show that villin controls the size of the F-actin cages restricting SGs and, thus, regulates their dynamics and availability for exocytosis. Evidence that villin acts downstream of Ica512 also indicates that SGs directly influence the remodeling properties of the cortical actin cytoskeleton for tight control of insulin secretion. Ica512-depletion reduces the genetic expression of the F-actin modifier villin. Villin-depletion enhances basal insulin granule mobility and exocytosis. Villin regulates the size of actin cages restraining insulin granules. Villin acts downstream of insulin granule cargo Ica512. The Ica512-villin genetic link enables granules to control cytoskeleton plasticity.
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DOI：
10.1083/jcb.146.4.819
发表时间：
1999-08-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ferrary E;Cohen-Tannoudji M;Pehau-Arnaudet G;Lapillonne A;Athman R;Ruiz T;Boulouha L;El Marjou F;Doye A;Fontaine JJ;Antony C;Babinet C;Louvard D;Jaisser F;Robine S
通讯作者：
Robine S
影响因子：
21.3
作者：
Knoch, KP;Bergert, H;Solimena, M
通讯作者：
Solimena, M
影响因子：
3.4
作者：
Hermel, JM;Dirkx, R;Solimena, M
通讯作者：
Solimena, M
DOI：
10.1073/pnas.89.9.3775
发表时间：
1992-05-01
影响因子：
11.1
作者：
CASTELLINO, F;HEUSER, J;LUINI, A
通讯作者：
LUINI, A
影响因子：
8.2
作者：
Fava, E.;Dehghany, J.;Ouwendijk, J.;Mueller, A.;Niederlein, A.;Verkade, P.;Meyer-Hermann, M.;Solimena, M.
通讯作者：
Solimena, M.