Janardhan, A., Swigut, T., Hill, B., Myers, M. P., Skowronski, J. (January 2004) HIV-1 Nef binds the DOCK2-ELMO1 complex to activate rac and inhibit lymphocyte chemotaxis. PLoS Biol, 2 (1). E6. ISSN 1545-7885 (Electronic)
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Abstract
The infectious cycle of primate lentiviruses is intimately linked to interactions between cells of the immune system. Nef, a potent virulence factor, alters cellular environments to increase lentiviral replication in the host, yet the mechanisms underlying these effects have remained elusive. Since Nef likely functions as an adaptor protein, we exploited a proteomic approach to directly identify molecules that Nef targets to subvert the signaling machinery in T cells. We purified to near homogeneity a major Nef-associated protein complex from T cells and identified by mass spectroscopy its subunits as DOCK2-ELMO1, a key activator of Rac in antigen- and chemokine-initiated signaling pathways, and Rac. We show that Nef activates Rac in T cell lines and in primary T cells following infection with HIV-1 in the absence of antigenic stimuli. Nef activates Rac by binding the DOCK2-ELMO1 complex, and this interaction is linked to the abilities of Nef to inhibit chemotaxis and promote T cell activation. Our data indicate that Nef targets a critical switch that regulates Rac GTPases downstream of chemokine- and antigen-initiated signaling pathways. This interaction enables Nef to influence multiple aspects of T cell function and thus provides an important mechanism by which Nef impacts pathogenesis by primate lentiviruses.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Adaptor Proteins Signal Transducing metabolism Antigens CD28 biosynthesis Antigens CD3 biosynthesis Cell Movement Chemotaxis Epitopes chemistry Gene Products nef metabolism physiology Guanine Nucleotide Exchange Factors metabolism HIV-1 metabolism Humans Interleukin-2 metabolism Jurkat Cells Lentivirus genetics Lymphocytes cytology virology Mass Spectrometry methods Plasmids metabolism Protein Binding Proteomics methods Signal Transduction rac GTP-Binding Proteins chemistry metabolism rac1 GTP-Binding Protein chemistry |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA replication organism description > virus |
| CSHL Authors: | |
| Depositing User: | CSHL Librarian |
| Date: | January 2004 |
| Date Deposited: | 03 Feb 2012 15:54 |
| Last Modified: | 03 Feb 2012 15:54 |
| URI: | https://repository.cshl.edu/id/eprint/22399 |
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