Primate lentiviruses, such as human and simian immunodeficiency viruses (HIV & SIV), require diverse host cell machineries to replicate and to persist in the infected host. In particular, HIV and SIV encode an array of “accessory” proteins allowing them to evade innate and acquired mechanisms that the target cells and the host employ to resist infection. These proteins are essential for the full pathogenic potential of immunodeficiency viruses. Our overall-long term goal is to understand the interactions between HIV/SIV and the host cells, at a molecular level, with a particular focus on the accessory proteins.
Our recent efforts have been broadly aimed to identify cellular co-factors of HIV/SIV-encoded proteins, as well as of selected cellular proteins that can block HIV replication. By using advanced proteomic tools, we recently identified a novel multisubunit E3 ubiquitin ligase complex that is usurped by Vpr and Vpx accessory proteins to carry out their functions. Remarkably, this E3 enzyme is required for the abilities of primate lentiviruses to establish infection in monocyte-derived cell lineages. Thus, one goal of our current studies is to elucidate of the exact role(s) of this E3 enzyme for HIV/SIV replication, using proteomic, reverse genetic and cell biology approaches. Our other ongoing studies address molecular underpinnings of selected mechanisms that cells use to resist HIV infection. The knowledge gained will further our understanding of molecular pathogenesis by HIV and could lead to the identification of new targets for antivirals.
Yan, J., Hao, C., DeLucia, M., Swanson, S., Florens, L., Washburn, M.P., Ahn, J., Skowronski, J. (2015) Cyclin A2 - CDK regulates SAMHD1 phosphohydrolase domain. J Biol Chem. 290, 13279-13292. [PubMed]
Yan, J., Kaur, S., DeLucia, M., Hao, C., Meherns, Wang, C., Golczak, M., Swanson, S.K., Palczewski, K., Florens, L., Gronenborn, A.M., Washburn, M.P., Ahn, J. and Skowronski, J. (2013) Tetramerization controls SAMHD1 catalytic activity and inhibition of HIV infection. J. Biol. Chem. 288:10406-17. [PubMed]
Xiaoyun, J., Wu, Y., Yan, J., Mehrens, J., Yang, H., DeLucia, M., Hao, C., Gronenborn, A.M., Skowronski, J., Ahn, J. and Xiong, Y. (2013) Mechanism of Allosteric Activation of SAMHD1 by dGTP. Nat. Struct. Mol. Biol. 20:1304-9.2
Fregoso, O.I., Ahn, J., Wang, C., Mehrens, J., Skowronski, J., Emerman, M. (2013) Evolutionary Toggling of Vpx/Vpr Specificity Results in Divergent Recognition of the Restriction Factor SAMHD1. PLoS Pathogens 9: e1003496.[PubMed]
Hrecka, K., Hao, C., Gierszewska, M., Swanson, S.K., Kesik-Brodacka, M., Srivastava, S., Florens, L., Washburn, M.P. and Skowronski, J. (2011) Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474, 658-661.[PubMed]
Srivastava, S., Swanson, S.K., Manel, N., Florens, L., Washburn, M.P. and 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, e1000059. [PubMed]
Hrecka, K., Gierszewska, M., Srivastava, S., Kozaczkiewicz, L., Swanson, S.K., Florens, L., Washburn, M.P. and Skowronski, J. (2007) Lentiviral Vpr Usurps Cul4-DDB1 [VprBP] E3 Ubiquitin Ligase to Modulate Cell Cycle. Proc. Natl Acad. Sci. USA 104, 11778-11783. [PubMed]
Janardhan, A., Swigut, T., Hill, B., Myers, M.P. and Skowronski, J. (2004) HIV-1 Nef Binds the DOCK2-ELMO1 Complex to Activate Rac and Inhibit Lymphocyte Chemotaxis. PloS Biol. 2, 65-76. [PubMed]