A Specialized Mechanism of Translation Mediated by FXR1a-Associated MicroRNP in Cellular Quiescence

Mol Cell. 2016 Mar 3;61(5):760-773. doi: 10.1016/j.molcel.2016.02.013.

Abstract

MicroRNAs predominantly decrease gene expression; however, specific mRNAs are translationally upregulated in quiescent (G0) mammalian cells and immature Xenopus laevis oocytes by an FXR1a-associated microRNA-protein complex (microRNP) that lacks the microRNP repressor, GW182. Their mechanism in these conditions of decreased mTOR signaling, and therefore reduced canonical (cap-and-poly(A)-tail-mediated) translation, remains undiscovered. Our data reveal that mTOR inhibition in human THP1 cells enables microRNA-mediated activation. Activation requires shortened/no poly(A)-tail targets; polyadenylated mRNAs are partially activated upon PAIP2 overexpression, which interferes with poly(A)-bound PABP, precluding PABP-enhanced microRNA-mediated inhibition and canonical translation. Consistently, inhibition of PARN deadenylase prevents activation. P97/DAP5, a homolog of canonical translation factor, eIF4G, which lacks PABP- and cap binding complex-interacting domains, is required for activation, and thereby for the oocyte immature state. P97 interacts with 3' UTR-binding FXR1a-associated microRNPs and with PARN, which binds mRNA 5' caps, forming a specialized complex to translate recruited mRNAs in these altered canonical translation conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Argonaute Proteins / genetics
  • Argonaute Proteins / metabolism
  • Binding Sites
  • Cell Line
  • Cellular Senescence*
  • Eukaryotic Initiation Factor-4G / genetics
  • Eukaryotic Initiation Factor-4G / metabolism
  • Exoribonucleases / genetics
  • Exoribonucleases / metabolism
  • Gene Expression Profiling / methods
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Oocytes / metabolism*
  • Protein Biosynthesis*
  • Proteomics / methods
  • RNA Caps / genetics
  • RNA Caps / metabolism
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Ribonucleoproteins / genetics
  • Ribonucleoproteins / metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transfection
  • Xenopus laevis

Substances

  • 3' Untranslated Regions
  • AGO2 protein, human
  • Argonaute Proteins
  • EIF4G2 protein, human
  • Eukaryotic Initiation Factor-4G
  • FXR1 protein, human
  • MicroRNAs
  • PAIP2 protein, human
  • RNA Caps
  • RNA, Messenger
  • RNA-Binding Proteins
  • Repressor Proteins
  • Ribonucleoproteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Exoribonucleases
  • poly(A)-specific ribonuclease