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Vol. 14, Issue 10, 4162-4172, October 2003

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Inhibition of Translation and Induction of Apoptosis by Bunyaviral Nonstructural Proteins Bearing Sequence Similarity to Reaper

Daniel A. Colón-Ramos ^*, Pablo M. Irusta , Eugene C. Gan ^*, Michael R. Olson ^*, Jaewhan Song , Richard I. Morimoto , Richard M. Elliott , Mark Lombard ^¶, Robert Hollingsworth ^¶, J. Marie Hardwick , Gary K. Smith ^¶, and Sally Kornbluth ^* ||

^* Department of Pharmacology and Cancer Biology, C370 LSRC, Duke University Medical Center, Durham, North Carolina 27710; Departments of Pharmacology and Molecular Sciences, Johns Hopkins University Schools of Medicine and Public Health, Baltimore, Maryland 21205; Rice Institute for Biomedical Research, Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60208; Division of Virology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G11 5JR, Scotland, United Kingdom; and ^¶ GlaxoSmithKline, Research Triangle Park, North Carolina 27709

Submitted March 7, 2003; Revised May 26, 2003; Accepted May 27, 2003
Monitoring Editor: Tony Hunter

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.

^|| Corresponding author. E-mail address: kornb001{at}mc.duke.edu.

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