4EHP-independent repression of endogenous mRNAs by the RNA-binding protein GIGYF2

Nucleic Acids Res. 2018 Jun 20;46(11):5792-5808. doi: 10.1093/nar/gky198.

Abstract

Initially identified as a factor involved in tyrosine kinase receptor signaling, Grb10-interacting GYF protein 2 (GIGYF2) has later been shown to interact with the 5' cap-binding protein 4EHP as part of a translation repression complex, and to mediate post-transcriptional repression of tethered reporter mRNAs. A current model proposes that GIGYF2 is indirectly recruited to mRNAs by specific RNA-binding proteins (RBPs) leading to translation repression through its association with 4EHP. Accordingly, we recently observed that GIGYF2 also interacts with the miRNA-induced silencing complex and probably modulates its translation repression activity. Here we have further investigated how GIGYF2 represses mRNA function. In a tethering reporter assay, we identify three independent domains of GIGYF2 with repressive activity. In this assay, GIGYF2-mediated repression is independent of 4EHP but largely dependent on the CCR4/NOT complex that GIGYF2 recruits through multiple interfaces. Importantly, we show that GIGYF2 is an RBP and identify for the first time endogenous mRNA targets that recapitulate 4EHP-independent repression. Altogether, we propose that GIGYF2 has two distinct mechanisms of repression: one depends on 4EHP binding and mainly affects translation; the other is 4EHP-independent and involves the CCR4/NOT complex and its deadenylation activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Eukaryotic Initiation Factor-4E
  • HeLa Cells
  • Humans
  • Protein Biosynthesis*
  • Protein Domains
  • RNA Cap-Binding Proteins / metabolism
  • RNA Stability*
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism*
  • Ribonucleases / metabolism

Substances

  • Carrier Proteins
  • EIF4E2 protein, human
  • Eukaryotic Initiation Factor-4E
  • GIGYF2 protein, human
  • RNA Cap-Binding Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Ribonucleases
  • mRNA deadenylase