Abstract
Hypoxia selectively enhances mRNA translation despite suppressed mammalian target of rapamycin complex 1 activity, contributing to gene expression reprogramming that promotes metastasis and survival of cancer cells. Little is known about how this paradoxical control of translation occurs. Here, we report a new pathway that links hypoxia to selective mRNA translation. Transglutaminase 2 (TG2) is a hypoxia-inducible factor 1-inducible enzyme that alters the activity of substrate proteins by polyamination or crosslinking. Under hypoxic conditions, TG2 polyaminated eukaryotic translation initiation factor 4E (eIF4E)-bound eukaryotic translation initiation factor 4E-binding proteins (4EBPs) at conserved glutamine residues. 4EBP1 polyamination enhances binding affinity for Raptor, thereby increasing phosphorylation of 4EBP1 and cap-dependent translation. Proteomic analyses of newly synthesized proteins in hypoxic cells revealed that TG2 activity preferentially enhanced the translation of a subset of mRNA containing G/C-rich 5'UTRs but not upstream ORF or terminal oligopyrimidine motifs. These results indicate that TG2 is a critical regulator in hypoxia-induced selective mRNA translation and provide a promising molecular target for the treatment of cancers.
Highlights
Inadequate oxygen availability, termed hypoxia, is a common stress that cancer cells encounter during tumor progression
Among several translation-related proteins, we found that 4EBP1 is polyaminated in a Transglutaminase 2 (TG2)-dependent manner in cells under hypoxic conditions (Fig 1A)
ATP6V1C1, but it suppressed ATP6V1A and showed little effect on EXOC4 (Fig 7C), indicating that TG2-mediated translational control is hypoxia specific. Cancer cells reprogram their gene expression in response to hypoxic stress mainly through hypoxia-inducible factor 1 (HIF1)-mediated transcriptional regulation to adapt to adverse microenvironments
Summary
Inadequate oxygen availability, termed hypoxia, is a common stress that cancer cells encounter during tumor progression. Inhibition of translation is a critical response for tumor cell survival because translation is an ATP-consuming process that requires approximately one-third of all cellular ATP (Fahling, 2009; Chee et al, 2019). Eukaryotic translation initiation factor 4E (eIF4E) is a binding protein to the 59 cap structure of mRNA and, together with scaffolding protein eIF4G and RNA helicase eIF4A, forms the eIF4F complex. The formation of the eIF4F complex is, critical for cap-dependent translation initiation This rate-limiting step is regulated by interactions between eIF4E and eIF4E-binding proteins (4EBP1, -2, and -3). Despite suppressed mTORC1 activity under hypoxic conditions, mRNA translation of genes for cellular survival and metabolic reprogramming is enhanced in tumor cells (Spriggs et al, 2010). The detailed molecular mechanisms underlying the regulation of 4EBP phosphorylation in response to hypoxic stress are not fully understood
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