PT  - JOURNAL ARTICLE
AU  - Sung-Yup Cho
AU  - Seungun Lee
AU  - Jeonghun Yeom
AU  - Hyo-Jun Kim
AU  - Jin-Haeng Lee
AU  - Ji-Woong Shin
AU  - Mee-ae Kwon
AU  - Ki Baek Lee
AU  - Eui Man Jeong
AU  - Hee Sung Ahn
AU  - Dong-Myung Shin
AU  - Kyunggon Kim
AU  - In-Gyu Kim
TI  - Transglutaminase 2 mediates hypoxia-induced selective mRNA translation via polyamination of 4EBPs
AID  - 10.26508/lsa.201900565
DP  - 2020 Mar 01
TA  - Life Science Alliance
PG  - e201900565
VI  - 3
IP  - 3
4099  - https://www.life-science-alliance.org/content/3/3/e201900565.short
4100  - https://www.life-science-alliance.org/content/3/3/e201900565.full
SO  - Life Sci. Alliance2020 Mar 01; 3
AB  - 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.