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ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay

Masayuki Sakurai1, Yusuke Shiromoto1, Hiromitsu Ota1

  • 1The Wistar Institute, Philadelphia, Pennsylvania, USA.

Nature Structural & Molecular Biology
|April 25, 2017
PubMed

Insights

The ADAR1-p110 enzyme moves to the cytoplasm during cellular stress, where it protects anti-apoptotic mRNAs from degradation. This discovery reveals a new stress response pathway involving ADAR1-p110 and Staufen1.

Area of Science:

  • Molecular Biology
  • RNA Biology
  • Cellular Stress Response

Background:

  • ADAR1 has two isoforms, p150 and p110, both editing double-stranded RNA (dsRNA).
  • ADAR1-p150 is known to regulate cytoplasmic dsRNA sensing.
  • The nuclear ADAR1-p110 isoform's function remains largely uncharacterized.

Purpose of the Study:

  • To elucidate the biological function of the ADAR1-p110 isoform.
  • To investigate the role of ADAR1-p110 in cellular stress response pathways.

Main Methods:

  • Investigated stress-activated phosphorylation of ADAR1-p110.
  • Examined ADAR1-p110 nuclear export mediated by Exportin-5.
  • Analyzed ADAR1-p110 interaction with Staufen1 and its effect on mRNA decay.

Main Results:

  • Stress-activated MAP kinases (MKK6-p38-MSK) phosphorylate ADAR1-p110, promoting its nuclear export via Exportin-5.
  • Translocated ADAR1-p110 protects anti-apoptotic gene transcripts with 3'-untranslated-region dsRNA structures from degradation.
  • ADAR1-p110 competitively inhibits Staufen1 binding to dsRNA, antagonizing Staufen1-mediated mRNA decay.

Conclusions:

  • ADAR1-p110 plays a critical role in cellular survival during stress.
  • A novel stress-response mechanism is identified involving ADAR1-p110 and Staufen1 in regulating mRNA surveillance.
  • This pathway is crucial for maintaining the stability of mRNAs essential for stressed cell survival.

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