An ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA inhibits PKR activation

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Authors

SINIGAGLIA Ketty CHERIAN Anna DU Qiupei LACOVICH STRAŠIL Valentina VUKIĆ Dragana MELICHEROVÁ Janka MUSILOVÁ Pavla ZERAD Lisa STEJSKAL Stanislav MALIK Radek PROCHAZKA Jan BONDURAND Nadege SEDLACEK Radislav O'CONNELL Mary Anne KEEGAN Liam

Year of publication 2024
Type Article in Periodical
Magazine / Source Cell Reports
MU Faculty or unit

Central European Institute of Technology

Citation
Web https://www.sciencedirect.com/science/article/pii/S2211124724009689?via%3Dihub
Doi http://dx.doi.org/10.1016/j.celrep.2024.114618
Keywords RNA; RECOGNITION; DIMERIZATION; ELF2-ALPHA
Description Adar null mutant mouse embryos die with aberrant double-stranded RNA (dsRNA)-driven interferon induction, and Adar Mavs double mutants, in which interferon induction is prevented, die soon after birth. Protein kinase R (Pkr) is aberrantly activated in Adar Mavs mouse pup intestines before death, intestinal crypt cells die, and intestinal villi are lost. Adar Mavs Eifak2 (Pkr) triple mutant mice rescue all defects and have longterm survival. Adenosine deaminase acting on RNA 1 (ADAR1) and PKR co-immunoprecipitate from cells, suggesting PKR inhibition by direct interaction. AlphaFold studies on an inhibitory PKR dsRNA binding domain (dsRBD)-kinase domain interaction before dsRNA binding and on an inhibitory ADAR1 dsRBD3PKR kinase domain interaction on dsRNA provide a testable model of the inhibition. Wild-type or editing- inactive human ADAR1 expressed in A549 cells inhibits activation of endogenous PKR. ADAR1 dsRNA binding is required for, but is not sufficient for, PKR inhibition. Mutating the ADAR1 dsRBD3-PKR contact prevents co-immunoprecipitation, ADAR1 inhibition of PKR activity, and co-localization of ADAR1 and PKR in cells.
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