GCN2 adapts protein synthesis to scavenging-dependent growth.

TitleGCN2 adapts protein synthesis to scavenging-dependent growth.
Publication TypeJournal Article
Year of Publication2022
AuthorsNofal, M, Wang, T, Yang, L, Jankowski, CSR, Li, SHsin-Jung, Han, S, Parsons, L, Frese, AN, Gitai, Z, Anthony, TG, Wühr, M, Sabatini, DM, Rabinowitz, JD
JournalCell Syst
Volume13
Issue2
Pagination158-172.e9
Date Published2022 02 16
ISSN2405-4720
KeywordsAmino Acids, Animals, Cathepsin L, Mice, Pancreatic Neoplasms, Protein Serine-Threonine Kinases, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Abstract

<p>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.</p>

DOI10.1016/j.cels.2021.09.014
Alternate JournalCell Syst
PubMed ID34706266
PubMed Central IDPMC8961722
Grant ListDP1 DK113643 / DK / NIDDK NIH HHS / United States
DP1 AI124669 / AI / NIAID NIH HHS / United States
R35 GM128813 / GM / NIGMS NIH HHS / United States
F31 CA186513 / CA / NCI NIH HHS / United States
R01 DK109714 / DK / NIDDK NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States