title: Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements.
abstract: The zinc finger protein tristetraprolin (TTP) promotes translation repression and degradation of mRNAs containing AU-rich elements (AREs). Although much attention has been directed toward understanding the decay process and machinery involved, the translation repression role of TTP has remained poorly understood. Here we identify the cap-binding translation repression 4EHP-GYF2 complex as a cofactor of TTP. Immunoprecipitation and in vitro pull-down assays demonstrate that TTP associates with the 4EHP-GYF2 complex via direct interaction with GYF2, and mutational analyses show that this interaction occurs via conserved tetraproline motifs of TTP. Mutant TTP with diminished 4EHP-GYF2 binding is impaired in its ability to repress a luciferase reporter ARE-mRNA. 4EHP knockout mouse embryonic fibroblasts (MEFs) display increased induction and slower turnover of TTP-target mRNAs as compared to wild-type MEFs. Our work highlights the function of the conserved tetraproline motifs of TTP and identifies 4EHP-GYF2 as a cofactor in translational repression and mRNA decay by TTP.
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Fu
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Myanna T
authors.initials: MT
authors.lastname: Olsen
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Kristofor
authors.initials: K
authors.lastname: Webb
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bennett
authors.affiliation: Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Lykke-Andersen
mesh_terms: D063307:AU Rich Elements; D000818:Animals; D002460:Cell Line; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D006868:Hydrolysis; D051379:Mice; D018345:Mice, Knockout; D011392:Proline / Q000378:metabolism*; D011485:Protein Binding; D012315:RNA Caps / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D051816:Tristetraprolin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D012315:RNA Caps; D012333:RNA, Messenger; D012097:Repressor Proteins; D051816:Tristetraprolin; C000597857:eIF4E2 protein, mouse; D011392:Proline
keywords: ARE-mediated decay; AU-rich elements; mRNA turnover; translation repression; tristetraprolin