Proteasomal degradation of WT proinsulin in pancreatic beta cells.
Proteasomal degradation of WT proinsulin in pancreatic beta cells.
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胰腺β细胞中WT蛋白质蛋白的蛋白酶体降解。
DOI：
10.1016/j.jbc.2022.102406
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发表时间：
2022-10
影响因子：
4.8
通讯作者：
Arvan, Peter
中科院分区：
文献类型：
--
作者：
Xu, Xiaoxi;Arunagiri, Anoop;Haataja, Leena;Alam, Maroof;Ji, Shuhui;Qi, Ling;Tsai, Billy;Liu, Ming;Arvan, Peter
胰岛素前原进入内质网产生胰岛素前原，随后将其传递到远端分泌途径，导致成熟胰岛素的加工、储存和分泌。多个研究小组已经报道，用蛋白酶体抑制剂治疗胰腺β细胞系、啮齿动物胰岛或人类胰岛会导致胰岛素原和胰岛素蛋白水平降低，葡萄糖刺激的胰岛素分泌减少，并改变β细胞基因表达，最终导致β细胞死亡。然而，这些研究大多检查的治疗时间远远超过了实现急性蛋白酶体抑制所需的时间。在这里，我们报道，尽管蛋白酶体抑制会立即下调新的胰岛素原的生物合成，但它仍然会急剧增加胰腺β细胞系、啮齿动物胰岛和人类胰岛中的β细胞胰岛素原水平，表明挽救了最近合成的WT INS基因产物库，否则这些基因产物将被蛋白酶体处理。我们的药理学证据表明，这种处置很可能反映了正在进行的内质网相关蛋白降解。然而，我们发现在蛋白酶体抑制后的60分钟内，细胞内胰岛素原水平开始下降，同时真核起始因子2 α磷酸化增加，这可以通过阻断一般控制的非抑制2激酶来抑制。总之，这些数据表明，新合成的INS基因产物的一个有意义的亚部分经历了快速的蛋白酶体处理。我们认为，来自蛋白酶体蛋白水解的游离氨基酸可能潜在地参与抑制一般控制的非抑制2激酶活性，以维持正在进行的胰岛素原生物合成。
Preproinsulin entry into the endoplasmic reticulum yields proinsulin, and its subsequent delivery to the distal secretory pathway leads to processing, storage, and secretion of mature insulin. Multiple groups have reported that treatment of pancreatic beta cell lines, rodent pancreatic islets, or human islets with proteasome inhibitors leads to diminished proinsulin and insulin protein levels, diminished glucose-stimulated insulin secretion, and changes in beta-cell gene expression that ultimately lead to beta-cell death. However, these studies have mostly examined treatment times far beyond that needed to achieve acute proteasomal inhibition. Here, we report that although proteasomal inhibition immediately downregulates new proinsulin biosynthesis, it nevertheless acutely increases beta-cell proinsulin levels in pancreatic beta cell lines, rodent pancreatic islets, and human islets, indicating rescue of a pool of recently synthesized WT INS gene product that would otherwise be routed to proteasomal disposal. Our pharmacological evidence suggests that this disposal most likely reflects ongoing endoplasmic reticulum–associated protein degradation. However, we found that within 60 min after proteasomal inhibition, intracellular proinsulin levels begin to fall in conjunction with increased phosphorylation of eukaryotic initiation factor 2 alpha, which can be inhibited by blocking the general control nonderepressible 2 kinase. Together, these data demonstrate that a meaningful subfraction of newly synthesized INS gene product undergoes rapid proteasomal disposal. We propose that free amino acids derived from proteasomal proteolysis may potentially participate in suppressing general control nonderepressible 2 kinase activity to maintain ongoing proinsulin biosynthesis.
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