A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions
A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions
复制标题
cullin 4B-RING E3 连接酶复合物微调胰腺 delta 细胞旁分泌相互作用
DOI：
10.1172/jci91348
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发表时间：
2017-06-30
影响因子：
15.9
通讯作者：
Yu, Xiao
中科院分区：
文献类型：
--
作者：
Li, Qing;Cui, Min;Yu, Xiao
胰腺δ细胞分泌的生长抑素介导胰岛中重要的旁分泌相互作用，包括通过控制胰岛素和胰高血糖素的相互分泌来维持葡萄糖代谢。这一循环的中断有助于糖尿病的发展。然而，控制胰岛分泌生长抑素的确切机制仍然难以捉摸。在这里，我们发现，一个超级复合物包括cullin 4 B-RING E3连接酶（CRL 4 B）和polycomb抑制复合物2（PRC 2）表观遗传调节生长抑素分泌的胰岛。CUL 4 B，CRL 4 B-PRC 2复合物的核心成分，在d细胞中的组成性消融通过增强生长抑素释放损害葡萄糖耐量和减少胰岛素分泌。此外，机制研究表明，CRL 4 B-PRC 2复合物在d细胞特异性转录因子造血表达的同源异型盒（HHEX）的控制下，通过组蛋白翻译后修饰决定细胞内钙和cAMP的水平，从而改变Cav1.2钙通道和腺苷酸环化酶6（AC 6）的表达并调节生长抑素分泌。在响应高葡萄糖水平或尿皮质素3（UCN 3）刺激，cullin 4 B（CUL 4 B）和PRC 2亚基组蛋白-赖氨酸N-甲基转移酶EZH 2的表达增加和Cav1.2和AC 6表达的相互减少被发现调节生长抑素分泌。我们的研究结果揭示了d细胞旁分泌相互作用的表观遗传调节机制，其中CRL 4 B-PRC 2复合物，Cav1.2和AC 6表达微调生长抑素分泌，促进胰岛中葡萄糖稳态。
Somatostatin secreted by pancreatic delta cells mediates important paracrine interactions in Langerhans islets, including maintenance of glucose metabolism through the control of reciprocal insulin and glucagon secretion. Disruption of this circuit contributes to the development of diabetes. However, the precise mechanisms that control somatostatin secretion from islets remain elusive. Here, we found that a super-complex comprising the cullin 4B-RING E3 ligase (CRL4B) and polycomb repressive complex 2 (PRC2) epigenetically regulates somatostatin secretion in islets. Constitutive ablation of CUL4B, the core component of the CRL4B-PRC2 complex, in d cells impaired glucose tolerance and decreased insulin secretion through enhanced somatostatin release. Moreover, mechanistic studies showed that the CRL4B-PRC2 complex, under the control of the d cell-specific transcription factor hematopoietically expressed homeobox (HHEX), determines the levels of intracellular calcium and cAMP through histone posttranslational modifications, thereby altering expression of the Cav1.2 calcium channel and adenylyl cyclase 6 (AC6) and modulating somatostatin secretion. In response to high glucose levels or urocortin 3 (UCN3) stimulation, increased expression of cullin 4B (CUL4B) and the PRC2 subunit histone-lysine N-methyltransferase EZH2 and reciprocal decreases in Cav1.2 and AC6 expression were found to regulate somatostatin secretion. Our results reveal an epigenetic regulatory mechanism of d cell paracrine interactions in which CRL4B-PRC2 complexes, Cav1.2, and AC6 expression fine-tune somatostatin secretion and facilitate glucose homeostasis in pancreatic islets.