Leucine aminopeptidase LyLAP enables lysosomal degradation of membrane proteins

• 成果类型: Article
• 署名作者: Jain, Aakriti; Heremans, Isaac; Rademaker, Gilles; Detomasi, Tyler C.; Rohweder, Peter; Anderson, Dashiell; Zhang, Justin; Hernandez, Grace A.; Gupta, Suprit; von Linde, Teresa; Lange, Mike; Spacci, Martina; Luo, Jiayi; Citron, Y. Rose; Olzmann, James A.; Dawson, David W.; Craik, Charles S.; Bommer, Guido; Perera, Rushika M.; Zoncu, Roberto
• 署名单位: University of California System; University of California Berkeley; Universite Catholique Louvain; Universite Catholique Louvain; WELBIO; University of California System; University of California San Francisco; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of California System; University of California San Francisco; University of California System; University of California Berkeley; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; UCLA Jonsson Comprehensive Cancer Center; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8691
• DOI: 10.1126/science.adq8331
• 发表日期: 2025-03-28
• 关键词: pancreatic-cancer; cysteine cathepsins; gene-expression; methyl-ester; autophagy; identification; ubiquitin; endocytosis; turnover; PATHWAY

摘要

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.