An ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA inhibits PKR activation
Year: 2024
Type: article
Abstract: 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 long-term 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 dsRBD3-PKR 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.
Source: Cell Reports
Language: English
Topic: RNA regulation and disease
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: Agence Nationale de la Recherche, Ministerstvo Školství, Mládeže a Tělovýchovy, Grantová Agentura České Republiky, Akademie Věd České Republiky, Central European Institute of Technology, RECETOX Přírodovědecké Fakulty Masarykovy Univerzity, Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences
Awards: G1751328538, G19608704, A mouse genetic model to study the control of interferon and inflammation, National Infrastructure for Biological and Medical Imaging, G2255957435, G252385833, Elucidating the role of the RNA editing enzyme ADAR1 in novel biological pathways and determine its posttranslational regulation., ADAR1 and RNA editing in development and maintenance of peripheral nervous system, G5097284512, G7148052796
OpenAlex ID: W4401564102