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

Masayuki Sakurai, Yusuke Shiromoto, Hiromitsu Ota, Chunzi Song, Andrew V. Kossenkov, Jayamanna Wickramasinghe, Louise C. Showe, Emmanuel Skordalakes, Hsin Yao Tang, David W. Speicher, Kazuko Nishikura

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37 Citations (Scopus)

Abstract

Both p150 and p110 isoforms of ADAR1 convert adenosine to inosine in double-stranded RNA (dsRNA). ADAR1p150 suppresses the dsRNA-sensing mechanism that activates MDA5-MAVS-IFN signaling in the cytoplasm. In contrast, the biological function of the ADAR1p110 isoform, which is usually located in the nucleus, is largely unknown. Here, we show that stress-activated phosphorylation of ADAR1p110 by MKK6-p38-MSK MAP kinases promotes its binding to Exportin-5 and its export from the nucleus. After translocating to the cytoplasm, ADAR1p110 suppresses apoptosis in stressed cells by protecting many antiapoptotic gene transcripts that contain 3′-untranslated-region dsRNA structures primarily comprising inverted Alu repeats. ADAR1p110 competitively inhibits binding of Staufen1 to the 3′-untranslated-region dsRNAs and antagonizes Staufen1-mediated mRNA decay. Our study reveals a new stress-response mechanism in which human ADAR1p110 and Staufen1 regulate surveillance of a set of mRNAs required for survival of stressed cells.

Original languageEnglish
Pages (from-to)534-543
Number of pages10
JournalNature Structural and Molecular Biology
Volume24
Issue number6
DOIs
Publication statusPublished - 2017 Jun 6

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Sakurai, M., Shiromoto, Y., Ota, H., Song, C., Kossenkov, A. V., Wickramasinghe, J., Showe, L. C., Skordalakes, E., Tang, H. Y., Speicher, D. W., & Nishikura, K. (2017). ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay. Nature Structural and Molecular Biology, 24(6), 534-543. https://doi.org/10.1038/nsmb.3403