Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation

Reed Brendan; Crawford Frances; Hill Ryan C.; Jin Niyun; White Janice; Krovi S. Harsha; Marrack Philippa; Hansen Kirk; Kappler John W.

首页> 外文期刊>The British journal of psychiatry : >Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation

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Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation

机译：溶酶体组织蛋白酶通过跨缺陷产生糖尿病CD4 T细胞的嵌合表位

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The identification of the peptide epitopes presented by major histocompatibility complex class II (MHCII) molecules that drive the CD4 T cell component of autoimmune diseases has presented a formidable challenge over several decades. In type 1 diabetes (T1D), recent insight into this problem has come from the realization that several of the important epitopes are not directly processed from a protein source, but rather pieced together by fusion of different peptide fragments of secretory granule proteins to create new chimeric epitopes. We have proposed that this fusion is performed by a reverse proteolysis reaction called transpeptidation, occurring during the catabolic turnover of pancreatic proteins when secretory granules fuse with lysosomes (crinophagy). Here, we demonstrate several highly antigenic chimeric epitopes for diabetogenic CD4 T cells that are produced by digestion of the appropriate inactive fragments of the granule proteins with the lysosomal protease cathepsin L (Cat-L). This pathway has implications for how self-tolerance can be broken peripherally in T1D and other autoimmune diseases.

机译：几十年来，识别主要组织相容性复合物II类（MHCII）分子所呈现的肽表位是一项艰巨的挑战，MHCII分子驱动自身免疫性疾病的CD4 T细胞成分。在1型糖尿病（T1D）中，最近对这个问题的认识来自于认识到几个重要的表位不是直接从蛋白质来源处理的，而是通过融合分泌颗粒蛋白的不同肽片段来拼合在一起，以创建新的嵌合表位。我们提出，这种融合是通过一种称为转肽的反向蛋白水解反应进行的，当分泌颗粒与溶酶体融合时，在胰腺蛋白质的分解代谢转换过程中发生（crinophagy）。在这里，我们展示了几种糖尿病CD4 T细胞的高度抗原嵌合表位，这些表位是由溶酶体蛋白酶组织蛋白酶L（Cat-L）消化颗粒蛋白的适当非活性片段产生的。这一途径对T1D和其他自身免疫性疾病的外周自我耐受如何被破坏具有重要意义。

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《The British journal of psychiatry :》 |2021年第2期|共21页
作者
Reed Brendan; Crawford Frances; Hill Ryan C.; Jin Niyun; White Janice; Krovi S. Harsha; Marrack Philippa; Hansen Kirk; Kappler John W.;
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Natl Jewish Hlth Dept Biomed Res Denver CO 80206 USA;

Natl Jewish Hlth Dept Biomed Res Denver CO 80206 USA;

Univ Colorado Biochem &

Mol Genet Anschutz Med Campus Aurora CO 80045 USA;

Natl Jewish Hlth Dept Biomed Res Denver CO 80206 USA;

Natl Jewish Hlth Dept Biomed Res Denver CO 80206 USA;

Natl Jewish Hlth Dept Biomed Res Denver CO 80206 USA;

Natl Jewish Hlth Dept Biomed Res Denver CO 80206 USA;

Univ Colorado Biochem &

Mol Genet Anschutz Med Campus Aurora CO 80045 USA;

Natl Jewish Hlth Dept Biomed Res Denver CO 80206 USA;

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正文语种 eng
中图分类精神病学;
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6. Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation [J] . Brendan Reed, Frances Crawford, Ryan C. Hill, The Journal of Experomental Medicine . 2021,第2期

机译：溶酶体组织素通过跨缺陷产生糖尿病CD4 T细胞的嵌合表位
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Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation

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