A network of RNA-binding proteins controls translation efficiency to activate anaerobic metabolism

J. J. David Ho, Nathan C. Balukoff, Phaedra R. Theodoridis, Miling Wang, Jonathan R. Krieger, Jonathan H. Schatz and Stephen Lee ()
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J. J. David Ho: University of Miami
Nathan C. Balukoff: University of Miami
Phaedra R. Theodoridis: University of Miami
Miling Wang: University of Miami
Jonathan R. Krieger: The SickKids Proteomics, Analytics, Robotics & Chemical Biology Centre (SPARC Biocentre), The Hospital for Sick Children
Jonathan H. Schatz: University of Miami
Stephen Lee: University of Miami

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Protein expression evolves under greater evolutionary constraint than mRNA levels, and translation efficiency represents a primary determinant of protein levels during stimuli adaptation. This raises the question as to the translatome remodelers that titrate protein output from mRNA populations. Here, we uncover a network of RNA-binding proteins (RBPs) that enhances the translation efficiency of glycolytic proteins in cells responding to oxygen deprivation. A system-wide proteomic survey of translational engagement identifies a family of oxygen-regulated RBPs that functions as a switch of glycolytic intensity. Tandem mass tag-pulse SILAC (TMT-pSILAC) and RNA sequencing reveals that each RBP controls a unique but overlapping portfolio of hypoxic responsive proteins. These RBPs collaborate with the hypoxic protein synthesis apparatus, operating as a translation efficiency checkpoint that integrates upstream mRNA signals to activate anaerobic metabolism. This system allows anoxia-resistant animals and mammalian cells to initiate anaerobic glycolysis and survive hypoxia. We suggest that an oxygen-sensitive RBP cluster controls anaerobic metabolism to confer hypoxia tolerance.

Date: 2020
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DOI: 10.1038/s41467-020-16504-1

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