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Journal of Virology, July 2006, p. 6267-6275, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.02177-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cumulative Mutations of Ubiquitin Acceptor Sites in Human Immunodeficiency Virus Type 1 Gag Cause a Late Budding Defect

Eva Gottwein,{dagger} Stefanie Jäger, Anja Habermann, and Hans-Georg Kräusslich*

Abteilung Virologie, Universitätsklinikum Heidelberg, D-69120 Heidelberg, Germany

Received 17 October 2005/ Accepted 5 April 2006

The p6 domain of human immunodeficiency virus type 1 (HIV-1) Gag has long been known to be monoubiquitinated. We have previously shown that the MA, CA, and NC domains are also monoubiquitinated at low levels (E. Gottwein and H. G. Krausslich, J. Virol. 79:9134-9144, 2005). While several lines of evidence support a role for ubiquitin in virus release, the relevance of Gag ubiquitination is unclear. To directly address the function of Gag ubiquitination, we constructed Gag variants in which lysine residues in the NC, SP2, and p6 domains were mutated to arginine either in individual domains or in combination. Using these mutants, we showed that in addition to MA, CA, NC, and p6, SP2 is also mono- or diubiquitinated at levels comparable to those of the other domains. Replacement of all lysine residues in only one of the domains had minor effects on virus release, while cumulative mutations in NC and SP2 or in NC and p6 resulted in an accumulation of late budding structures, as observed by electron microscopy analysis. Strikingly, replacement of all lysine residues downstream of CA led to a significant reduction in virus release kinetics and a fivefold accumulation of late viral budding structures compared to wild-type levels. These results indicate that ubiquitination of lysine residues in Gag in the vicinity of the viral late domain is important for HIV-1 budding, while no specific lysine residue may be needed and individual domains can functionally substitute. This is consistent with Gag ubiquitination being functionally involved in a transient protein interaction network at the virus budding site.

* Corresponding author. Mailing address: Abteilung Virologie, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany. Phone: 49-6221-565001. Fax: 49-6221-565003. E-mail: Hans-Georg.Kraeusslich{at}med.uni-heidelberg.de.

{dagger} Present address: Department of Microbiology and Genetics, Box 3025, Duke University Medical Center, Durham, NC 27710.

Journal of Virology, July 2006, p. 6267-6275, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.02177-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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