Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing.
Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing.
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DOI：
10.1038/ncomms16014
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发表时间：
2017-07-12
影响因子：
16.6
通讯作者：
Bernal-Mizrachi E
中科院分区：
文献类型：
--
作者：
Blandino-Rosano M;Barbaresso R;Jimenez-Palomares M;Bozadjieva N;Werneck-de-Castro JP;Hatanaka M;Mirmira RG;Sonenberg N;Liu M;Rüegg MA;Hall MN;Bernal-Mizrachi E
解除mTOR复合物1 （mTORC1）信号的调控会增加代谢性疾病的风险，包括2型糖尿病。本研究通过条件型（βraKO）和诱导型（MIP-βraKOf/f） raptor缺失小鼠，发现β细胞特异性mTORC1缺失导致β细胞增殖、自噬、凋亡和胰岛素分泌缺陷导致糖尿病和β细胞衰竭。通过mTORC1下游靶点的基因重构，我们发现mTORC1/S6K通路是mTORC1调控β-细胞凋亡、大小和自噬的机制，而mTORC1/ 4e - bp2 - eif4e通路调控β-细胞增殖的机制。这两种途径的恢复部分恢复β细胞质量和高血糖。该研究还证明了mTORC1通过以4EBP2/ eif4e依赖的方式调节羧基肽酶E的帽依赖性翻译，在控制胰岛素加工过程中发挥核心作用。雷帕霉素治疗降低小鼠和人胰岛CPE表达和胰岛素分泌。我们认为mTORC1在β细胞中发挥重要作用，并确定了驱动β细胞质量、功能和胰岛素加工的下游途径。mTORC1通路的失调与几种人类疾病有关，包括糖尿病、神经变性和癌症。这里Blandino-Rosano等人表明mTORC1信号通过调节β细胞增殖、凋亡、自噬和胰岛素加工来控制胰岛素分泌和β细胞维持。
Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that β-cell-specific loss of mTORC1 causes diabetes and β-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (βraKO) and inducible (MIP-βraKOf/f) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates β-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates β-cell proliferation. Restoration of both pathways partially recovers β-cell mass and hyperglycaemia. This study also demonstrates a central role of mTORC1 in controlling insulin processing by regulating cap-dependent translation of carboxypeptidase E in a 4EBP2/eIF4E-dependent manner. Rapamycin treatment decreases CPE expression and insulin secretion in mice and human islets. We suggest an important role of mTORC1 in β-cells and identify downstream pathways driving β-cell mass, function and insulin processing. Deregulation of mTORC1 pathway has been associated with several human diseases including diabetes, neurodegeneration and cancer. Here Blandino-Rosano et al. show that mTORC1 signalling controls insulin secretion and β-cell maintenance by regulation of β-cell proliferation, apoptosis and autophagy and insulin processing.
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