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Journal of Virology, December 2004, p. 13865-13870, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13865-13870.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Prototype Foamy Virus Envelope Glycoprotein Leader Peptide Processing Is Mediated by a Furin-Like Cellular Protease, but Cleavage Is Not Essential for Viral Infectivity

Anja Duda,^1, Annett Stange,^1, Daniel Lüftenegger,¹ Nicole Stanke,¹ Dana Westphal,¹ Thomas Pietschmann,^2, Scott W. Eastman,^3, Maxine L. Linial,³ Axel Rethwilm,² and Dirk Lindemann^1*

Institut für Virologie, Medizinische Fakultät "Carl Gustav Carus," Technische Universität Dresden, Dresden,¹ Institut für Virologie und Immunbiologie, Universität Würzburg, Würzburg, Germany,² Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, Washington³

Received 3 June 2004/ Accepted 26 July 2004

Analogous to cellular glycoproteins, viral envelope proteins contain N-terminal signal sequences responsible for targeting them to the secretory pathway. The prototype foamy virus (PFV) envelope (Env) shows a highly unusual biosynthesis. Its precursor protein has a type III membrane topology with both the N and C terminus located in the cytoplasm. Coexpression of FV glycoprotein and interaction of its leader peptide (LP) with the viral capsid is essential for viral particle budding and egress. Processing of PFV Env into the particle-associated LP, surface (SU), and transmembrane (TM) subunits occur posttranslationally during transport to the cell surface by yet-unidentified cellular proteases. Here we provide strong evidence that furin itself or a furin-like protease and not the signal peptidase complex is responsible for both processing events. N-terminal protein sequencing of the SU and TM subunits of purified PFV Env-immunoglobulin G immunoadhesin identified furin consensus sequences upstream of both cleavage sites. Mutagenesis analysis of two overlapping furin consensus sequences at the PFV LP/SU cleavage site in the wild-type protein confirmed the sequencing data and demonstrated utilization of only the first site. Fully processed SU was almost completely absent in viral particles of mutants having conserved arginine residues replaced by alanines in the first furin consensus sequence, but normal processing was observed upon mutation of the second motif. Although these mutants displayed a significant loss in infectivity as a result of reduced particle release, no correlation to processing inhibition was observed, since another mutant having normal LP/SU processing had a similar defect.

A.D. and A.S. contributed equally.

Present address: Hygiene Institut, Abteilung Molekulare Virologie, Universität Heidelberg, Heidelberg, Germany.

Present address: Aaron Diamond AIDS Research Center, New York, N.Y.

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