GCN2 adapts protein synthesis to scavenging-dependent growth.

Cell systems 2022 Feb 16

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Pancreatic cancer cells with limited access to free amino acids can grow by scavenging extracellular protein. In a murine model of pancreatic cancer, we performed a genome-wide CRISPR screen for genes required for scavenging-dependent growth. The screen identified key mediators of macropinocytosis, peripheral lysosome positioning, endosome-lysosome fusion, lysosomal protein catabolism, and translational control. The top hit was GCN2, a kinase that suppresses translation initiation upon amino acid depletion. Using isotope tracers, we show that GCN2 is not required for protein scavenging. Instead, GCN2 prevents ribosome stalling but without slowing protein synthesis; cells still use all of the limiting amino acids as they emerge from lysosomes. GCN2 also adapts gene expression to the nutrient-poor environment, reorienting protein synthesis away from ribosomes and toward lysosomal hydrolases, such as cathepsin L. GCN2, cathepsin L, and the other genes identified in the screen are potential therapeutic targets in pancreatic cancer. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Michel Nofal, Tim Wang, Lifeng Yang, Connor S R Jankowski, Sophia Hsin-Jung Li, Seunghun Han, Lance Parsons, Alexander N Frese, Zemer Gitai, Tracy G Anthony, Martin Wühr, David M Sabatini, Joshua D Rabinowitz. GCN2 adapts protein synthesis to scavenging-dependent growth. Cell systems. 2022 Feb 16;13(2):158-172.e9