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J. Virol. doi:10.1128/JVI.01238-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

NSm protein of Rift Valley Fever Virus Suppresses Virus-induced Apoptosis

Department of Microbiology and Immunology and Pathology, University of Texas Medical Branch at Galveston, Galveston, Texas 77555-1019

^* To whom correspondence should be addressed. Email: shmakino{at}utmb.edu.

	Abstract

Rift Valley fever virus (RVFV) is a member of the genus Phlebovirus within the family Bunyaviridae and can cause severe epidemics among ruminants and fever, myalgia, a hemorrhagic syndrome, and/or encephalitis in humans. The RVFV M segment encodes the NSm and 78-kDa proteins and two major envelope proteins Gn and Gc. The biological functions of the NSm and 78-kDa proteins are unknown, while both proteins are dispensable for viral replication in cell cultures. To determine the biological functions of the NSm and 78-kDa proteins, we generated the mutant virus arMP-12-del21/384, carrying a large deletion in the pre-Gn region of the M segment. Neither the NSm nor 78-kDa proteins were synthesized in arMP-12-del21/384-infected cells. Although arMP-12-del21/384 and its parental arMP-12 showed similar virus growth kinetics, viral RNA and protein accumulation in infected cells, arMP-12-del21/384-infected cells induced extensive cell death and produced larger plaques than did the arMP-12-infected cells. arMP-12-del21/384 replication triggered apoptosis, including caspase-3 cleavage, the cleavage of its downstream substrate, poly-ADP-ribose polymerase, and activations of initiator caspases, caspase-8 and -9, early in infection as compared with arMP-12. NSm expression in arMP-12-del21/384-infected cells suppressed the severity of caspase-3 activation. Further, NSm protein expression inhibited the staurosporine-induced activation of caspase-8 and -9, demonstrating that other viral proteins were dispensable for the NSm's function in inhibiting apoptosis. RVFV NSm protein is the first identified Phlebovirus protein that has an antiapoptotic function.

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