Top-Down Proteomics of Mouse Islets With Beta Cell CPE Deletion Reveals Molecular Details in Prohormone Processing.
Top-Down Proteomics of Mouse Islets With Beta Cell CPE Deletion Reveals Molecular Details in Prohormone Processing.
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DOI：
10.1210/endocr/bqad160
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发表时间：
2023-11-02
期刊：
影响因子：
4.8
通讯作者：
Qian, Wei-Jun
中科院分区：
文献类型：
--
作者：
Fulcher, James M.;Swensen, Adam C.;Chen, Yi-Chun;Verchere, C. Bruce;Petyuk, Vladislav A.;Qian, Wei-Jun
激素前加工的改变，如胰岛素前和胰岛淀粉样多肽前（proIAPP），已被报道为糖尿病前期和糖尿病的一个重要特征。胰岛素原加工包括去除几个c端碱性氨基酸，主要由外肽酶羧肽酶E （CPE）完成，CPE或其他激素原转化酶（PC1/3和PC2）的突变导致高胰岛素原血症。胰岛中Cpe缺失后不正确处理的胰岛素和其他激素产物的形式和数量的综合表征尚未尝试。在本研究中，我们应用自顶向下的蛋白质组学在β细胞特异性Cpe敲除小鼠模型中对激素加工中间体的多种蛋白质形态进行了全局评估。我们发现含有二碱基残基的胰岛素原和其他加工不当的胰岛素原的新蛋白形式增加，我们可以将几种加工后的蛋白形式归类为CPE的新底物。有趣的是，尽管缺失了CPE，但其他一些已知的CPE底物仍未受到影响，这意味着羧基肽酶D （CPD）等旁系加工酶可以弥补CPE的损失，并维持接近正常水平的激素加工。总之，我们自上而下的胰岛蛋白质组学的定量结果为激素加工产物的复杂性和调节机制提供了独特的见解。
Altered prohormone processing, such as with proinsulin and pro-islet amyloid polypeptide (proIAPP), has been reported as an important feature of prediabetes and diabetes. Proinsulin processing includes removal of several C-terminal basic amino acids and is performed principally by the exopeptidase carboxypeptidase E (CPE), and mutations in CPE or other prohormone convertase enzymes (PC1/3 and PC2) result in hyperproinsulinemia. A comprehensive characterization of the forms and quantities of improperly processed insulin and other hormone products following Cpe deletion in pancreatic islets has yet to be attempted. In the present study we applied top-down proteomics to globally evaluate the numerous proteoforms of hormone processing intermediates in a β-cell-specific Cpe knockout mouse model. Increases in dibasic residue–containing proinsulin and other novel proteoforms of improperly processed proinsulin were found, and we could classify several processed proteoforms as novel substrates of CPE. Interestingly, some other known substrates of CPE remained unaffected despite its deletion, implying that paralogous processing enzymes such as carboxypeptidase D (CPD) can compensate for CPE loss and maintain near normal levels of hormone processing. In summary, our quantitative results from top-down proteomics of islets provide unique insights into the complexity of hormone processing products and the regulatory mechanisms.
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