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

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, usually located in the nucleus, remains largely unknown. Here we show that stress-activated phosphorylation of ADAR1p110 by MKK6-p38-MSK MAP kinases promotes its binding to Exportin-5 and export from the nucleus. Once translocated to the cytoplasm, ADAR1p110 suppresses apoptosis of stressed cells by protecting many anti-apoptotic gene transcripts that contain 3′UTR dsRNA structures primarily made from inverted Alu repeats. ADAR1p110 competitively inhibits binding of Staufen1 to the 3′UTR dsRNAs and antagonizes the Staufen1-mediated mRNA decay. Our studies revealed a new stress response mechanism, in which human ADAR1p110 and Staufen1 regulate surveillance of a set of mRNAs required for survival of stressed cells.