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Journal of Virology, January 2006, p. 342-352, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.342-352.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Interaction of Moloney Murine Leukemia Virus Capsid with Ubc9 and PIASy Mediates SUMO-1 Addition Required Early in Infection

Andrew Yueh,1,{dagger} Juliana Leung,2 Subarna Bhattacharyya,1,{ddagger} Lucy A. Perrone,1,§ Kenia de los Santos,1 Szy-yuan Pu,3 and Stephen P. Goff1*

Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032,1 Integrated Program in Cellular, Molecular, and Biophysical Studies, College of Physicians and Surgeons, Columbia University, New York, New York 10032,2 National Health Research Institutes, Division of Biotechnology and Pharmaceutical Research, Taipai, Taiwan, Republic of China3

Received 12 May 2005/ Accepted 2 October 2005

Yeast two-hybrid screens led to the identification of Ubc9 and PIASy, the E2 and E3 small ubiquitin-like modifier (SUMO)-conjugating enzymes, as proteins interacting with the capsid (CA) protein of the Moloney murine leukemia virus. The binding site in CA for Ubc9 was mapped by deletion and alanine-scanning mutagenesis to a consensus motif for SUMOylation at residues 202 to 220, and the binding site for PIASy was mapped to residues 114 to 176, directly centered on the major homology region. Expression of CA and a tagged SUMO-1 protein resulted in covalent transfer of SUMO-1 to CA in vivo. Mutations of lysine residues to arginines near the Ubc9 binding site and mutations at the PIASy binding site reduced or eliminated CA SUMOylation. Introduction of these mutations into the complete viral genome blocked virus replication. The mutants exhibited no defects in the late stages of viral gene expression or virion assembly. Upon infection, the mutant viruses were able to carry out reverse transcription to synthesize normal levels of linear viral DNA but were unable to produce the circular viral DNAs or integrated provirus normally found in the nucleus. The results suggest that the SUMOylation of CA mediated by an interaction with Ubc9 and PIASy is required for early events of infection, after reverse transcription and before nuclear entry and viral DNA integration.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032. Phone: (212) 305-3794. Fax: (212) 305-5106. E-mail: goff{at}cancercenter.columbia.edu.

{dagger} Present address: National Health Research Institutes, Division of Biotechnology and Pharmaceutical Research, Taipai, Taiwan, ROC.

{ddagger} Present address: Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY 10021.

§ Present address: University of Texas Medical Branch, Department of Pathology, Galveston, TX 77555.

Journal of Virology, January 2006, p. 342-352, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.342-352.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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