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A more recent version of this article appeared on October 1, 2003
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Submitted on March 7, 2003
Revised on May 26, 2003
Accepted on May 27, 2003
1 Department of Pharmacology and Cancer Biology, Box
3813, C370 LSRC, Research Drive, Duke University Medical Center,
Durham, NC 27710; PH: 919-613-8624, FAX: 919-681-1005;
kornb001@mc.duke.edu
2 Departments of Pharmacology and
Molecular Sciences, Johns Hopkins University Schools of Medicine and
Public Health, 615 North Wolfe St., Baltimore, Maryland 21205, USA
3 Rice Institute for Biomedic Biochemistry, Molecular
Biology, and Cell Biology, Northwestern University, 2153 North Campus
Drive, Evanston, IL 60208, USA
4 Division of Virology,
Institute of Biomedical and Life Sciences, University of Glasgow,
Church Street, Glasgow G11 5JR, Scotland, United Kingdom
5 GlaxoSmithKline 5 Moore Dr., Research Triangle Park, NC
27709
* Corresponding author. E-mail address: kornb001{at}mc.duke.edu.
Members of the California serogroup of bunyaviruses (family Bunyaviridae) are the leading cause of pediatric viral encephalitis in North America. Significant cell death is observed as part of the infection pathology. We now report that a Bunyaviral NonStructural protein termed NSs shows sequence similarity to Reaper, a proapoptotic protein from Drosophila. Although NSs proteins lack the Reaper N-terminal motif critical for IAP inhibition, they do retain other functions of Reaper that map to conserved C-terminal regions. Like Reaper, NSs proteins induce mitochondrial cytochrome c release and caspase activation in cell-free extracts, and promote neuronal apoptosis and mortality in a mouse model. Independent of caspase activation, Bunyavirus NSs proteins also share with Reaper the ability to directly inhibit cellular protein translation. We have found that the shared capacity to inhibit translation and induce apoptosis resides in common sequence motifs present in both Reaper and NSs proteins. Data presented here suggest that NSs induce apoptosis through a mechanism similar to that used by Reaper, as both proteins bind to an apoptotic regulator called Scythe and can relieve Scythe inhibition of Hsp70. Thus, bunyavirus NSs proteins have multiple Reaper-like functions that likely contribute to viral pathogenesis by promoting cell death and/or inhibiting cellular translation.
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