METHODS: We characterized three novel PNLIP variants in transfected cells by assessing their secretion, intracellular distribution, and markers of endoplasmic reticulum (ER) stress.
RESULTS: All three variants had secretion defects. Notably, the p.R188C and p.W419∗ variants induced misfolding of PNLIP and accumulated as detergent-insoluble aggregates resulting in elevated BiP at both protein and mRNA levels indicating increased ER stress.
CONCLUSIONS: All three novel PNLIP variants cause a loss-of-function through impaired secretion. Additionally, the p.R188C and p.W419∗ variants may induce proteotoxicity through misfolding and potentially increase the risk for pancreatic acinar cell injury.
方法:我们通过评估三种新的PNLIP变体在转染细胞中的分泌特性,细胞内分布,和内质网(ER)应激的标志物。
结果:所有三种变体都有分泌缺陷。值得注意的是,p.R188C和p.W419*变体诱导PNLIP的错误折叠,并作为洗涤剂不溶性聚集体积累,导致蛋白质和mRNA水平的BiP升高,表明ER应激增加。
结论:所有三种新型PNLIP变异体均通过分泌受损导致功能丧失。此外,p.R188C和p.W419*变体可能通过错误折叠诱导蛋白毒性,并可能增加胰腺腺泡细胞损伤的风险。