Oxygen-Sensitive Remodeling of Central Carbon Metabolism by Archaic eIF5B

J. J.David Ho, Nathan C. Balukoff, Grissel Cervantes, Petrice D. Malcolm, Jonathan R. Krieger, Stephen Lee

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The eukaryotic translation initiation factor 5B (eIF5B) is a homolog of IF2, an ancient translation factor that enables initiator methionine-tRNAi Met (met-tRNAi Met ) loading on prokaryotic ribosomes. While it can be traced back to the last universal common ancestor, eIF5B is curiously dispensable in modern aerobic yeast and mammalian cells. Here, we show that eIF5B is an essential element of the cellular hypoxic cap-dependent protein synthesis machinery. System-wide interrogation of dynamic translation machineries by MATRIX (mass spectrometry analysis of active translation factors using ribosome density fractionation and isotopic labeling experiments) demonstrated augmented eIF5B activity in hypoxic translating ribosomes. Global translatome studies revealed central carbon metabolism, cellular hypoxic adaptation, and ATF4-mediated stress response as major eIF5B-dependent pathways. These primordial processes rely on eIF5B even in the presence of oxygen and active eIF2, the canonical recruiter of met-tRNAi Met in eukaryotes. We suggest that aerobic eukarya retained eIF5B/IF2 to remodel anaerobic pathways during episodes of oxygen deficiency. Ho et al. employed MATRIX to demonstrate that eIF5B is an essential hypoxic translation factor that facilitates met-tRNAi Met delivery to ribosomes, serving as the hypoxic surrogate of the textbook eIF2. Aerobic eukarya likely retained eIF5B for the oxygen-dependent regulation of central carbon metabolism and hypoxic survival.

Original languageEnglish (US)
Pages (from-to)17-26
Number of pages10
JournalCell Reports
Volume22
Issue number1
DOIs
StatePublished - Jan 2 2018

Keywords

  • ATF4
  • IF2
  • MATRIX
  • carbon metabolism
  • eIF5B
  • evolution
  • glycolysis
  • hypoxia
  • stress
  • translation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ho, J. J. D., Balukoff, N. C., Cervantes, G., Malcolm, P. D., Krieger, J. R., & Lee, S. (2018). Oxygen-Sensitive Remodeling of Central Carbon Metabolism by Archaic eIF5B. Cell Reports, 22(1), 17-26. https://doi.org/10.1016/j.celrep.2017.12.031