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Journal of Virology, October 2005, p. 12643-12649, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12643-12649.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Endocytosis Plays a Critical Role in Proteolytic Processing of the Hendra Virus Fusion Protein

Kelly Ann Meulendyke, Mark Allen Wurth, Richard O. McCann, and Rebecca Ellis Dutch*

Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536-0298

Received 10 May 2005/ Accepted 20 July 2005

The Hendra virus fusion (F) protein is synthesized as a precursor protein, F0, which is proteolytically processed to the mature form, F1+F2. Unlike the case for the majority of paramyxovirus F proteins, the processing event is furin independent, does not require the addition of exogenous proteases, is not affected by reductions in intracellular Ca2+, and is strongly affected by conditions that raise the intracellular pH (C. T. Pager, M. A. Wurth, and R. E. Dutch, J. Virol. 78:9154-9163, 2004). The Hendra virus F protein cytoplasmic tail contains a consensus motif for endocytosis, YXX{Phi}. To analyze the potential role of endocytosis in the processing and membrane fusion promotion of the Hendra virus F protein, mutation of tyrosine 525 to alanine (Hendra virus F Y525A) or phenylalanine (Hendra virus F Y525F) was performed. The rate of endocytosis of Hendra virus F Y525A was significantly reduced compared to that of the wild-type (wt) F protein, confirming the functional importance of the endocytosis motif. An intermediate level of endocytosis was observed for Hendra virus F Y525F. Surprisingly, dramatic reductions in the rate of proteolytic processing were observed for Hendra virus F Y525A, although initial transport to the cell surface was not affected. The levels of surface expression for both Hendra virus F Y525A and Hendra virus F Y525F were higher than that of the wt protein, and these mutants displayed enhanced syncytium formation. These results suggest that endocytosis is critically important for Hendra virus F protein cleavage, representing a new paradigm for proteolytic processing of paramyxovirus F proteins.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, 741 S. Limestone, BBSRB, Lexington, KY 40536-0509. Phone: (859) 323-1795. Fax: (859) 323-1037. E-mail: rdutc2{at}uky.edu.

Journal of Virology, October 2005, p. 12643-12649, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12643-12649.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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