title: Tristetraprolin Recruits Eukaryotic Initiation Factor 4E2 To Repress Translation of AU-Rich Element-Containing mRNAs.
abstract: Tristetraprolin (TTP) regulates the expression of AU-rich element-containing mRNAs through promoting the degradation and repressing the translation of target mRNA. While the mechanism for promoting target mRNA degradation has been extensively studied, the mechanism underlying translational repression is not well established. Here, we show that TTP recruits eukaryotic initiation factor 4E2 (eIF4E2) to repress target mRNA translation. TTP interacted with eIF4E2 but not with eIF4E. Overexpression of eIF4E2 enhanced TTP-mediated translational repression, and downregulation of endogenous eIF4E2 or overexpression of a truncation mutant of eIF4E2 impaired TTP-mediated translational repression. Overexpression of an eIF4E2 mutant that lost the cap-binding activity also impaired TTP's activity, suggesting that the cap-binding activity of eIF4E2 is important in TTP-mediated translational repression. We further show that TTP promoted eIF4E2 binding to target mRNA. These results imply that TTP recruits eIF4E2 to compete with eIF4E to repress the translation of target mRNA. This notion is supported by the finding that downregulation of endogenous eIF4E2 increased the production of tumor necrosis factor alpha (TNF-α) protein without affecting the mRNA levels in THP-1 cells. Collectively, these results uncover a novel mechanism by which TTP represses target mRNA translation.
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Xianzun
authors.initials: X
authors.lastname: Tao
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China gaogx@moon.ibp.ac.cn.
authors.forename: Guangxia
authors.initials: G
authors.lastname: Gao
mesh_terms: D063307:AU Rich Elements; D015536:Down-Regulation; D039561:Eukaryotic Initiation Factor-4E; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D014176:Protein Biosynthesis; D060066:Protein Interaction Maps; D039381:RNA Cap-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051816:Tristetraprolin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C112609:EIF4E2 protein, human; D039561:Eukaryotic Initiation Factor-4E; D039381:RNA Cap-Binding Proteins; D012333:RNA, Messenger; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha