RT Journal Article SR Electronic T1 Transglutaminase 2 mediates hypoxia-induced selective mRNA translation via polyamination of 4EBPs JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201900565 DO 10.26508/lsa.201900565 VO 3 IS 3 A1 Cho, Sung-Yup A1 Lee, Seungun A1 Yeom, Jeonghun A1 Kim, Hyo-Jun A1 Lee, Jin-Haeng A1 Shin, Ji-Woong A1 Kwon, Mee-ae A1 Lee, Ki Baek A1 Jeong, Eui Man A1 Ahn, Hee Sung A1 Shin, Dong-Myung A1 Kim, Kyunggon A1 Kim, In-Gyu YR 2020 UL http://www.life-science-alliance.org/content/3/3/e201900565.abstract 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.