2. Academic Validation
  3. GCN2 adapts protein synthesis to scavenging-dependent growth

GCN2 adapts protein synthesis to scavenging-dependent growth

  • Cell Syst. 2022 Feb 16;13(2):158-172.e9. doi: 10.1016/j.cels.2021.09.014.
Michel Nofal 1,  Tim Wang 2,  Lifeng Yang 1,  Connor S R Jankowski 3,  Sophia Hsin-Jung Li 4,  Seunghun Han 1,  Lance Parsons 5,  Alexander N Frese 6,  Zemer Gitai 4,  Tracy G Anthony 7,  Martin Wühr 6,  David M Sabatini 2,  Joshua D Rabinowitz 8
Affiliations

Affiliations

  • 1 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
  • 2 Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 3 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 4 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 5 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
  • 6 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 7 Department of Nutritional Sciences and the New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ 08901, USA.
  • 8 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Chemistry, Princeton University, Princeton, NJ 08544, USA; Ludwig Institute for Cancer Research, Princeton Branch, Princeton University, Princeton, NJ 08540, USA. Electronic address: joshr@princeton.edu.
PMID: 34706266 DOI: 10.1016/j.cels.2021.09.014
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.

Keywords

Cathepsin L; GCN2; PDAC; lysosomes; macropinocytosis; protein scavenging; protein synthesis; translation.

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