Aberrant activation of the innate immune sensor PKR by self dsRNA is prevented by direct interaction with ADAR1

Abstract

SummaryLoss of dsRNA editing by Adar1 leads to aberrant interferon induction inAdarnull mouse embryos.Adar Mavsmutants, in which this interferon induction is prevented, die within two weeks of birth. We show here that early death of pups is reduced inAdar Mavs EIF2αk2(Pkr) mutants, identifying PKR as the second aberrantly activated dsRNA sensor inAdarmutant mice. In intestines ofAdar Mavspups transit amplifying progenitor cells in intestinal crypts die and intestinal villi are lost in pups before death; intestinal defects are prevented inAdar Mavs Eifak2. In human A549 lung cancer cells ADAR1 forms a complex with PKR. AlphaFold modelling predicts a direct inhibitory interaction of ADAR1 dsRBDIII with the PKR near the kinase active site and a new mode for ADAR1 dsRNA-binding. Mutations at residues required for ADAR1 dsRNA binding or for predicted PKR contacts, prevent interaction with PKR.