Exosome cofactor hMTR4 competes with export adaptor ALYREF to ensure balanced nuclear RNA pools for degradation and export

EMBO J. 2017 Oct 2;36(19):2870-2886. doi: 10.15252/embj.201696139. Epub 2017 Aug 11.


The exosome is a key RNA machine that functions in the degradation of unwanted RNAs. Here, we found that significant fractions of precursors and mature forms of mRNAs and long noncoding RNAs are degraded by the nuclear exosome in normal human cells. Exosome-mediated degradation of these RNAs requires its cofactor hMTR4. Significantly, hMTR4 plays a key role in specifically recruiting the exosome to its targets. Furthermore, we provide several lines of evidence indicating that hMTR4 executes this role by directly competing with the mRNA export adaptor ALYREF for associating with ARS2, a component of the cap-binding complex (CBC), and this competition is critical for determining whether an RNA is degraded or exported to the cytoplasm. Together, our results indicate that the competition between hMTR4 and ALYREF determines exosome recruitment and functions in creating balanced nuclear RNA pools for degradation and export.

Keywords: ALYREF; ARS2; hMTR4; mRNA export; nuclear RNA degradation.

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Exosome Multienzyme Ribonuclease Complex / genetics
  • Exosome Multienzyme Ribonuclease Complex / metabolism
  • Exosomes / genetics
  • Exosomes / metabolism
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • RNA Helicases / genetics
  • RNA Helicases / metabolism*
  • RNA Stability* / genetics
  • RNA Transport / genetics*
  • RNA, Long Noncoding / metabolism
  • RNA, Messenger / metabolism
  • RNA, Nuclear / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • ALYREF protein, human
  • Nuclear Proteins
  • RNA, Long Noncoding
  • RNA, Messenger
  • RNA, Nuclear
  • RNA-Binding Proteins
  • Transcription Factors
  • Exosome Multienzyme Ribonuclease Complex
  • MTREX protein, human
  • RNA Helicases