[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Jain, Aakriti ; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA
Heremans, Isaac ; Metabolic Research Group, de Duve Institute and WELBIO, Universite Catholique de Louvain, Brussels, Belgium
Rademaker, Gilles ; Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory ; Department of Anatomy and Helen Diller Cancer Center, University of California, San Francisco, San Francisco, CA, USA
Detomasi, Tyler C ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
Rohweder, Peter ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
Anderson, Dashiell; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
Zhang, Justin; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA
Hernandez, Grace A ; Department of Anatomy and Helen Diller Cancer Center, University of California, San Francisco, San Francisco, CA, USA
Gupta, Suprit ; Department of Anatomy and Helen Diller Cancer Center, University of California, San Francisco, San Francisco, CA, USA
von Linde, Teresa ; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA
Lange, Mike; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA ; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA
Spacci, Martina ; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA
Luo, Jiayi ; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA
Citron, Y Rose; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA
Olzmann, James A ; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA ; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA
Dawson, David W ; Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA
Craik, Charles S ; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
Bommer, Guido ; Metabolic Research Group, de Duve Institute and WELBIO, Universite Catholique de Louvain, Brussels, Belgium
Perera, Rushika M; Department of Anatomy and Helen Diller Cancer Center, University of California, San Francisco, San Francisco, CA, USA
Zoncu, Roberto ; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA
