TY - JOUR T1 - Transglutaminase 2 mediates hypoxia-induced selective mRNA translation via polyamination of 4EBPs JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900565 VL - 3 IS - 3 SP - e201900565 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 Y1 - 2020/03/01 UR - https://www.life-science-alliance.org/content/3/3/e201900565.abstract N2 - 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. ER -