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Journal of Virology, May 2008, p. 4898-4907, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.02675-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Efficient and Specific Rescue of Human Immunodeficiency Virus Type 1 Budding Defects by a Nedd4-Like Ubiquitin Ligase {triangledown}

Yoshiko Usami, Sergei Popov, Elena Popova, and Heinrich G. Göttlinger*

Program in Gene Function and Expression, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Received 17 December 2007/ Accepted 21 February 2008

To exit infected cells, human immunodeficiency virus type 1 (HIV-1) exploits the vacuolar protein-sorting pathway by engaging Tsg101 and ALIX through PTAP and LYPxnL late assembly (L) domains. In contrast, less-complex retroviruses often use PPxY L domains to recruit Nedd4 family ubiquitin ligases. Although HIV-1 Gag lacks PPxY motifs, we now show that the budding of various HIV-1 L-domain mutants is dramatically enhanced by ectopic Nedd4-2s, a native isoform with a truncated C2 domain. The effect of Nedd4-2s on HIV-1 budding required a catalytically active HECT domain and was specific, since other Nedd4 family proteins showed little activity and an unrelated retrovirus was not rescued. The residual C2 domain of Nedd4-2s was critical for the enhancement of HIV-1 budding and for the association of Nedd4-2s with Gag, as reflected by its incorporation into virus-like particles. Interestingly, the incorporation of Nedd4-2s also depended on its active site, indicating that the ability to form a thioester with ubiquitin was required. These data suggest a novel mechanism by which HIV-1 Gag can connect to cellular budding machinery.

* Corresponding author. Mailing address: UMass Medical School, LRB 526, 364 Plantation Street, Worcester, MA 01605. Phone: (508) 856-2843. Fax: (508) 856-4650. E-mail: heinrich.gottlinger{at}umassmed.edu

{triangledown} Published ahead of print on 5 March 2008.

Journal of Virology, May 2008, p. 4898-4907, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.02675-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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