Lentiviral Vpx accessory factor targets VprBP/DCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligase to enable macrophage infection

Srivastava, S., Swanson, S. K., Manel, N., Florens, L., Washburn, M. P., Skowronski, J. (2008) Lentiviral Vpx accessory factor targets VprBP/DCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligase to enable macrophage infection. PLoS Pathog, 4 (5). e1000059.

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URL: http://www.ncbi.nlm.nih.gov/pubmed/18464893
DOI: 10.1371/journal.ppat.1000059

Abstract

Vpx is a small virion-associated adaptor protein encoded by viruses of the HIV-2/SIVsm lineage of primate lentiviruses that enables these viruses to transduce monocyte-derived cells. This probably reflects the ability of Vpx to overcome an as yet uncharacterized block to an early event in the virus life cycle in these cells, but the underlying mechanism has remained elusive. Using biochemical and proteomic approaches, we have found that Vpx protein of the pathogenic SIVmac 239 strain associates with a ternary protein complex comprising DDB1 and VprBP subunits of Cullin 4-based E3 ubiquitin ligase, and DDA1, which has been implicated in the regulation of E3 catalytic activity, and that Vpx participates in the Cullin 4 E3 complex comprising VprBP. We further demonstrate that the ability of SIVmac as well as HIV-2 Vpx to interact with VprBP and its associated Cullin 4 complex is required for efficient reverse transcription of SIVmac RNA genome in primary macrophages. Strikingly, macrophages in which VprBP levels are depleted by RNA interference resist SIVmac infection. Thus, our observations reveal that Vpx interacts with both catalytic and regulatory components of the ubiquitin proteasome system and demonstrate that these interactions are critical for Vpx ability to enable efficient SIVmac replication in primary macrophages. Furthermore, they identify VprBP/DCAF1 substrate receptor for Cullin 4 E3 ubiquitin ligase and its associated protein complex as immediate downstream effector of Vpx for this function. Together, our findings suggest a model in which Vpx usurps VprBP-associated Cullin 4 ubiquitin ligase to enable efficient reverse transcription and thereby overcome a block to lentivirus replication in monocyte-derived cells, and thus provide novel insights into the underlying molecular mechanism.

Item Type: Paper
Uncontrolled Keywords: Adaptor Proteins, Signal Transducing/metabolism Animals CD4-Positive T-Lymphocytes/virology Cell Line Cullin Proteins/*antagonists & inhibitors/metabolism Fluoresceins/*metabolism Gene Expression Regulation, Viral Gene Products, vpr/*metabolism Humans Leukocytes, Mononuclear/cytology/drug effects Macrophage Colony-Stimulating Factor/pharmacology Macrophages/*virology Signal Transduction Simian immunodeficiency virus/pathogenicity/*physiology Ubiquitin-Protein Ligases/*antagonists & inhibitors/metabolism Viral Regulatory and Accessory Proteins/chemistry/*metabolism
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types
organs, tissues, organelles, cell types and functions > cell types and functions > cell types

organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > macrophages

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > ubiquitin ligase
organism description > virus
CSHL Authors:
Communities: CSHL labs > Skowronski lab
Depositing User: Matt Covey
Date Deposited: 26 Feb 2013 16:56
Last Modified: 26 Feb 2013 16:56
PMCID: PMC2330158
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27558

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