ADP-ribosyl–binding and hydrolase activities of the alphavirus nsP3 macrodomain are critical for initiation of virus replication

著者: Rachy Abraham, Debra Hauer, Robert Lyle McPherson, Age Utt, Ilsa T. Kirby, Michael S. Cohen, Andres Merits, Anthony K. L. Leung, Diane E. Griffin - Proceedings of the National Academy of Sciences, PNAS 2018 被引用: 142

Significance Alphaviruses are mosquito-borne RNA viruses that cause encephalitis, rash, and arthritis. Alphavirus nonstructural protein 3 (nsP3) has a highly conserved macrodomain that can bind and remove ADP-ribose (ADPr) residues from ADP-ribosylated proteins, but its role in virus replication was not known. We show that alphavirus replication in neural cells depends on protein ADP ribosylation and that nsP3s with mutations that eliminate ADPr binding cannot form a functional replicase. Mutations that decrease ADPr binding result in fewer infected cells, while mutations that increase binding but decrease hydrolase activity infect cells normally but amplify replication complexes less well. Therefore, alphavirus replication requires nsP3 macrodomain interaction with one or more ADP-ribosylated proteins, as is consistent with the observed high conservation of this region.