Leucine aminopeptidase LyLAP enables lysosomal degradation of membrane proteins

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-03-28 DOI:10.1126/science.adq8331

Aakriti Jain, Isaac Heremans, Gilles Rademaker, Tyler C. Detomasi, Peter Rohweder, Dashiell Anderson, Justin Zhang, Grace A. Hernandez, Suprit Gupta, Teresa von Linde, Mike Lange, Martina Spacci, Jiayi Luo, Y. Rose Citron, James A. Olzmann, David W. Dawson, Charles S. Craik, Guido Bommer, Rushika M. Perera, Roberto Zoncu

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Abstract

Breakdown of every transmembrane protein trafficked to lysosomes requires proteolysis of their hydrophobic helical transmembrane domains. Combining lysosomal proteomics with functional genomic datasets, we identified lysosomal leucine aminopeptidase (LyLAP; formerly phospholipase B domain–containing 1) as the hydrolase most tightly associated with elevated endocytosis. Untargeted metabolomics and biochemical reconstitution demonstrated that LyLAP is a processive monoaminopeptidase with preference for amino-terminal leucine. This activity was necessary and sufficient for the breakdown of hydrophobic transmembrane domains. LyLAP was up-regulated in pancreatic ductal adenocarcinoma (PDA), which relies on macropinocytosis for nutrient uptake. In PDA cells, LyLAP ablation led to the buildup of undigested hydrophobic peptides, lysosomal membrane damage, and growth inhibition. Thus, LyLAP enables lysosomal degradation of membrane proteins and protects lysosomal integrity in highly endocytic cancer cells.

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每一种转运到溶酶体的跨膜蛋白的分解都需要对其疏水螺旋跨膜结构域进行蛋白水解。通过溶酶体蛋白质组学与功能基因组数据集的结合，我们发现溶酶体亮氨酸氨肽酶（LyLAP；前身为含磷脂酶 B 结构域 1）是与内吞作用增强最密切相关的水解酶。非靶向代谢组学和生化重组表明，LyLAP 是一种偏好氨基末端亮氨酸的加工性单胺肽酶。这种活性是分解疏水性跨膜结构域的必要和充分条件。LyLAP在胰腺导管腺癌（PDA）中上调，而PDA依赖大蛋白胞吞作用摄取营养物质。在 PDA 细胞中，消减 LyLAP 会导致未消化的疏水肽堆积、溶酶体膜损伤和生长抑制。因此，LyLAP能使溶酶体降解膜蛋白，并保护高度内吞癌细胞溶酶体的完整性。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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