GCN2 adapts protein synthesis to scavenging-dependent growth

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)158-172.e9
JournalCell Systems
Volume13
Issue number2
DOIs
StatePublished - Feb 16 2022

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

Keywords

  • Cathepsin L
  • GCN2
  • PDAC
  • lysosomes
  • macropinocytosis
  • protein scavenging
  • protein synthesis
  • translation

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