Hybrid insulin peptide isomers spontaneously form in pancreatic beta-cells from an aspartic anhydride intermediate.
Hybrid insulin peptide isomers spontaneously form in pancreatic beta-cells from an aspartic anhydride intermediate.
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DOI：
10.1016/j.jbc.2023.105264
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发表时间：
2023-11
影响因子：
4.8
通讯作者：
Delong, Thomas
中科院分区：
文献类型：
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作者：
Crawford, Samantha A;Groegler, Jason;Dang, Mylinh;Michel, Cole;Powell, Roger L;Hohenstein, Anita C;Reyes, Kaitlin;Haskins, Kathryn;Wiles, Timothy A;Delong, Thomas
当胰岛素片段通过肽键与其他肽连接时，在β细胞中形成杂合胰岛素肽（HIP）。HIP含有非基因组氨基酸序列，并已被确定为1型糖尿病中自身反应性T细胞的靶点。通过质谱法在胰岛中检测到一个HIP亚组，其中各种肽的N-末端氨基与胰岛素C-肽的天冬氨酸残基连接。在这里，我们研究了一种新的机制，导致这些HIP在人类和小鼠胰岛的形成。我们在此的研究表明，这些HIP通过涉及天冬氨酸酐中间体的机制在β细胞中自发形成。该机制导致形成含有标准肽键的常规HIP以及通过连接至天冬氨酸残基的羧酸侧链而含有异肽键的HIP异构体。我们使用质谱分析来确认胰岛中两种HIP异构体的存在，从而验证β细胞中这种新型反应机制的发生。细胞内新肽键的自发形成可能导致新表位的发展，这些新表位有助于1型糖尿病以及其他自身免疫性疾病的发病机制。
Hybrid insulin peptides (HIPs) form in beta-cells when insulin fragments link to other peptides through a peptide bond. HIPs contain nongenomic amino acid sequences and have been identified as targets for autoreactive T cells in type 1 diabetes. A subgroup of HIPs, in which N-terminal amine groups of various peptides are linked to aspartic acid residues of insulin C-peptide, was detected through mass spectrometry in pancreatic islets. Here, we investigate a novel mechanism that leads to the formation of these HIPs in human and murine islets. Our research herein shows that these HIPs form spontaneously in beta-cells through a mechanism involving an aspartic anhydride intermediate. This mechanism leads to the formation of a regular HIP containing a standard peptide bond as well as a HIP-isomer containing an isopeptide bond by linkage to the carboxylic acid side chain of the aspartic acid residue. We used mass spectrometric analyses to confirm the presence of both HIP isomers in islets, thereby validating the occurrence of this novel reaction mechanism in beta-cells. The spontaneous formation of new peptide bonds within cells may lead to the development of neoepitopes that contribute to the pathogenesis of type 1 diabetes as well as other autoimmune diseases.