NSm protein of Rift Valley fever virus suppresses virus-induced apoptosis.
Rift Valley fever virus (RVFV) is a member of the genus Phlebovirus within the family Bunyaviridae. It 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; 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 NSm nor the 78-kDa protein was synthesized in arMP-12-del21/384-infected cells. Although arMP-12-del21/384 and its parental virus, arMP-12, showed similar growth kinetics and viral RNA and protein accumulation in infected cells, arMP-12-del21/384-infected cells induced extensive cell death and produced larger plaques than did arMP-12-infected cells. arMP-12-del21/384 replication triggered apoptosis, including the cleavage of caspase-3, the cleavage of its downstream substrate, poly(ADP-ribose) polymerase, and activation of the initiator caspases, caspase-8 and -9, earlier in infection than 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 NSm's function in inhibiting apoptosis. RVFV NSm protein is the first identified Phlebovirus protein that has an antiapoptotic function.
Won
Sungyong
S
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1019, USA.
Ikegami
Tetsuro
T
Peters
C J
CJ
Makino
Shinji
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000821:virology; D008264:Macrophages / Q000821:virology; D051379:Mice; D012367:RNA, Viral / Q000032:analysis; D012296:Rift Valley fever virus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity* / Q000502:physiology; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010948:Viral Plaque Assay; D014779:Virus Replication
D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D020169:Caspases