NSm protein of Rift Valley fever virus suppresses virus-induced apoptosis

J Virol. 2007 Dec;81(24):13335-45. doi: 10.1128/JVI.01238-07. Epub 2007 Oct 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Caspases / metabolism
  • Cell Line
  • Chlorocebus aethiops
  • Enzyme Activation / drug effects
  • Humans
  • Kidney / cytology
  • Kidney / virology
  • Macrophages / virology
  • Mice
  • RNA, Viral / analysis
  • Rift Valley fever virus / genetics
  • Rift Valley fever virus / metabolism
  • Rift Valley fever virus / pathogenicity*
  • Rift Valley fever virus / physiology
  • Vero Cells
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism
  • Viral Nonstructural Proteins / pharmacology*
  • Viral Plaque Assay
  • Virus Replication

Substances

  • RNA, Viral
  • Viral Nonstructural Proteins
  • Caspases