Transglutaminase 2 mediates hypoxia-induced selective mRNA translation via polyamination of 4EBPs

Sung Yup Cho, Seungun Lee, Jeonghun Yeom, Hyo Jun Kim, Jin Haeng Lee, Ji Woong Shin, Mee Ae Kwon, Ki Baek Lee, Eui Man Jeong, Hee Sung Ahn, Dong Myung Shin, Kyunggon Kim, In Gyu Kim

Research output: Contribution to journalArticle

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 59UTRs 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.

Original languageEnglish
Article numbere201900565
JournalLife Science Alliance
Volume3
Issue number3
DOIs
StatePublished - 1 Mar 2020

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    Cho, S. Y., Lee, S., Yeom, J., Kim, H. J., Lee, J. H., Shin, J. W., Kwon, M. A., Lee, K. B., Jeong, E. M., Ahn, H. S., Shin, D. M., Kim, K., & Kim, I. G. (2020). Transglutaminase 2 mediates hypoxia-induced selective mRNA translation via polyamination of 4EBPs. Life Science Alliance, 3(3), [e201900565]. https://doi.org/10.26508/lsa.201900565