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

M Sakurai, Y Shiromoto, H Ota, C Song… - Nature structural & …, 2017 - nature.com
M Sakurai, Y Shiromoto, H Ota, C Song, AV Kossenkov, J Wickramasinghe, LC Showe
Nature structural & molecular biology, 2017nature.com
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 …
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.
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