ADP-Ribosylhydrolase Activity of Chikungunya Virus Macrodomain Is Critical for Virus Replication and Virulence
ADP-ribosylhydrolase activity of Chikungunya virus macrodomain is critical for virus replication and virulence Robert Lyle McPhersona,1, Rachy Abrahamb,1, Easwaran Sreekumarb,1,2, Shao-En Ongc, Shang-Jung Chenga, Victoria K. Baxterb,d, Hans A. V. Kistemakere, Dmitri V. Filippove, Diane E. Griffinb,3, and Anthony K. L. Leunga,f,3 aDepartment of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205; bW. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205; cDepartment of Pharmacology, University of Washington, Seattle, WA 98195; dDepartment of Molecular and Comparative Pathobiology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205; eDepartment of Bio-organic Synthesis, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands; and fDepartment of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205 Contributed by Diane E. Griffin, January 5, 2017 (sent for review October 20, 2016; reviewed by William Lee Kraus and Susan R. Weiss) Chikungunya virus (CHIKV), an Old World alphavirus, is trans- N-terminal domain of nsP2 has helicase, ATPase, GTPase, mitted to humans by infected mosquitoes and causes acute rash methyltransferase, and 5′ triphosphatase activity. nsP4 is the and arthritis, occasionally complicated by neurologic disease and RNA-dependent RNA polymerase (4). chronic arthritis. One determinant of alphavirus virulence is non- The function of nsP3 has been more enigmatic. nsP3 is found structural protein 3 (nsP3) that contains a highly conserved MacroD- in replication complexes and cytoplasmic nonmembranous type macrodomain at the N terminus, but the roles of nsP3 and the granules.
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