Endoplasmic Reticulum Targeting Alters Regulation of Expression and Antigen Presentation of Proinsulin
Endoplasmic Reticulum Targeting Alters Regulation of Expression and Antigen Presentation of Proinsulin
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DOI：
10.4049/jimmunol.1300631
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发表时间：
2014-06-01
影响因子：
4.4
通讯作者：
van Endert, Peter
中科院分区：
文献类型：
--
作者：
Hsu, Hsiang-Ting;Janssen, Linda;van Endert, Peter
由MHC I类（MHC-I）分子呈现的肽配体是由蛋白酶体降解细胞质和核，以及内质网（ER）驻留蛋白产生的。然而，银内质网蛋白的加工仍然很少被描述。研究在自身免疫性糖尿病中起关键作用的胰岛素原的加工和提呈，我们发现靶向内质网不仅对胰岛素原的降解有深远的影响，而且对其细胞水平的调节也有深远的影响。虽然蛋白酶体抑制抑制了胞浆内胰岛素原的降解和呈现，但正如预期的那样，它降低了er靶向胰岛素原的丰度。这种靶向和蛋白质修饰修饰蛋白质半衰期也对mhc - 1的提呈和胰岛素原的蛋白水解加工有深远的影响。因此，稳定的管腔形式的呈现是低效的，但在蛋白酶体抑制下会增强，而不稳定的管腔形式和细胞质形式的呈现则更有效，但在蛋白酶体抑制剂的作用下会受到损害。细胞内和腔内胰岛素原产生的肽MHC复合物的不同稳定性表明，不同的蛋白水解活性处理两种Ag形式。因此，Ags的结构特征和亚细胞靶向性都可以对mhc - i限制性Ags参与的加工途径以及它们的呈递效率和调控产生强烈影响。
Peptide ligands presented by MHC class I (MHC-I) molecules are produced by degradation of cytosolic and nuclear, but also endoplasmic reticulum (ER)-resident, proteins by the proteasome. However, Ag processing of ER proteins remains little characterized. Studying processing and presentation of proinsulin, which plays a pivotal role in autoimmune diabetes, we found that targeting to the ER has profound effects not only on how proinsulin is degraded, but also on regulation of its cellular levels. While proteasome inhibition inhibited degradation and presentation of cytosolic proinsulin, as expected, it reduced the abundance of ER-targeted proinsulin. This targeting and protein modifications modifying protein half-life also had profound effects on MHC-I presentation and proteolytic processing of proinsulin. Thus, presentation of stable luminal forms was inefficient but enhanced by proteasome inhibition, whereas that of unstable luminal forms and of a cytosolic form were more efficient and compromised by proteasome inhibitors. Distinct stability of peptide MHC complexes produced from cytosolic and luminal proinsulin suggests that different proteolytic activities process the two Ag forms. Thus, both structural features and subcellular targeting of Ags can have strong effects on the processing pathways engaged by MHC-I-restricted Ags, and on the efficiency and regulation of their presentation.