Tom Hobman

Tom Hobman

Tom Hobman (Ph.D. University of British Columbia)

Professor

Department of Cell Biology
6-142K Katz Group - Rexall Centre for Pharmacy and Health Research
Phone: (780) 492-6485
Fax: (780) 492-0450 (fax)
tom.hobman@ualberta.ca


Awards

  • Canada Research Chair in RNA Viruses and Host Interactions

Research Interests

My laboratory is focused on the dynamics of celluar and viral ribonucleoprotein complexes; specifically, RNA interference effector complexes and viral capsid protein complexes.

Project 1: Dynamics of RNA interference effector complexes.
Argonaute proteins belong to a highly conserved superfamily found in virtually all eukaryotes. They form the cores of ribonucleoprotein complexes that mediate RNA interference (RNAi) and are thought to control the expression of more than half of all human genes. Specificity in Argonaute-dependent gene-silencing pathways is provided by short partially double-stranded microRNAs (miRNAs) that are transcribed from nuclear genes. MiRNA precursors are pre-processed in the nucleus and then exported to the cytoplasm where they are cleaved into mature miRNAs by the RNase, Dicer. Exogenous dsRNA can also be processed by Dicer leading to the generation of short interfering (siRNAs). MiRNAs and siRNAs are incorporated into Argonaute-containing gene-silencing complexes that associate with cytoplasmic foci called P-bodies or GW-bodies. We have recently shown that the molecular chaperone Hsp90 is required for assembly of Argonautes with Dicer, but is not part of mature gene-silencing complexes.

Live-cell imaging showing recruitment of GFP-labelled Argonaute 2 protein to nascent stress granules and P-bodies

Because of their central roles in regulating gene expression in mammalian cells, we believe that the functions of Argonaute proteins are subject to extensive regulation. Already it is known that for some Argonautes, their functions are regulated in part by subcellular localization. For example, the human Argonaute2 protein (hAgo2) functions in at least two different complexes in the nucleus and cytoplasm. However, it is not known how Argonautes are differentially targeted to gene-silencing complexes. Our central hypothesis is that the roles of Argonautes in gene-silencing and intracellular signaling pathways are regulated by differential subcellular localization. In the present application, we will focus on cis- and trans-acting factors that regulate Argonaute localization and function. To this end, we have identified Hsp90, the kinesin Cut7 and a number of protein kinases as putative regulators of Argonaute activity/localization.

Project 2: Non-structural functions of virus capsid proteins.
In addition to serving as building blocks of virions, some capsid proteins have nonstructural functions that regulate virus replication and disease development. We and others have shown that the capsid proteins of Rubella and West Nile viruses interact with a surprising number of host cell-encoded proteins. A number of these capsid-binding proteins have important functions in anti-viral signaling pathways. As such, we believe that the study of capsid-host cell protein interactions may provide important clues as to how viruses subvert the cellular anti-viral defense systems.

Rubella virus (RV) and West Nile virus (WNV) capsid are targeted to different organelles. Targeting of virus capsid to cellular organelles may be important for virus-host interactions.

We use a number of different approaches to study interactions between host cell proteins and viral capsids. First, capsid-binding proteins are identified by affinity purification or genetic screens. If a particular capsid-binding protein is not required for cell viability, RNA interference is used to down-regulate its expression and the viral replication is assessed under these conditions. For example, we have shown that a specific karyopherin is required for transport of the West Nile virus capsid into the nuclei of infected cells. To determine if interactions between capsid and a given host cell protein are important for virus replication, we produce dominant negative versions of the host cell protein that when over-expressed, will block interaction between capsid and the endogenous protein. In parallel, regions of capsid that interact with the host cell proteins are mapped and ablating mutations are introduced into the capsid gene of infectious molecular clones. Mutant viruses are generated and the replication characteristics of the viruses are analyzed. Our most recent studies are focused on the mechanisms by which capsid proteins inhibit or promote apoptosis.


Selected Publications

Ilkow, C. Willows, S. and Hobman, T.C. (2010) The Rubella Virus capsid protein: A small protein with big functions. Future Microbiology 5:571-84

Ilkow, C., Weckbecker, D., Maeir, S., Cho, WJ., Beatch, M. D., Goping, I.S., Herrmann, J., and Hobman, T. C. (2010) The Rubella virus capsid protein affects import of proteins into mitochondria. J. Virol. 84:119-30.

Stoica, C., Park, JS, Pare, J. M., Willows, S. and Hobman, T.C. (2010) The kinesin Cut7 regulates the size and morphology of Argonaute complexes. Traffic 11:25-36.

Pare, J.M., LópezOrozco, J. and Hobman, T.C. (2010) Live cell imaging of Argonaute proteins in mammalian cells. Argonaute Proteins: Methods in Molecular Biology, Humana Press, (eds. T.C. Hobman and T. Duchaine) in progress for 2010

Parker, H.R. and Hobman, T.C. (2010) RNA Domains in Cellular Domains, Wiley-Blackwell (ed. I.R. Nabi) in press.

Pare, J., Tahbaz, N., López-Orozco, J., LaPointe, P., Lasko, P. and Hobman, T. C. (2009) Hsp90 Regulates the Function of Argonaute 2 and its Recruitment to Stress Granules and P-bodies Mol. Biol. Cell 4:3273-84

Ilkow, C., Mancinelli, V., Beatch, M. D., and Hobman, T.C. (2008) Rubella virus capsid protein binds to the poly(A)-binding protein and inhibits translation. J. Virol 82:4284-94
Note: This article was selected by the editors for inclusion in "Spotlight," a feature in the Journal that highlights research articles of significant interest from the current issue.

Urbanowski, M.D., Ilkow, C.S. and Hobman, T. C. (2008) Modulation of Signaling Pathways by RNA Virus Capsid Proteins. Cell Signal 20:1227-36.

van Marle, G., Antony, J., Ostermann, H., Dunham, C., Hunt, T., Halliday, W., Maingat, F., Urbanowski, M.D., Hobman, T., Peeling, J., and Power, C. (2007) West Nile Virus-induced neuroinflammation: glial infection and capsid protein-mediated neurovirulence. J. Virol. 81: 10933-10949.

Hunt, T.A., Urbanowski, M., Kikani, K., Law, L.M., Brinton, M.A. and Hobman, T.C. (2007) Interactions between the West Nile Virus capsid protein and the host cell-encoded phosphatase inhibitor, I2PP2A. Cellular Microbiology (in press).

Stoica, C., Carmichael, J.B., Parker, H., Pare, J. and Hobman, T.C. (2006) The RNA interference effector protein Ago1 binds to 14-3-3 proteins and affects Cdc25-dependent cell cycle progression. J. Biol. Chem. 281:37646-51.

Schneider, M.D., Najand, N., Chaker, S. Pare, J., Haskins, J., Hughes, S.C., Hobman, T. C., Locke, J., Simmonds, A.J. (2006) Gawky is a component of cytoplasmic mRNA processing bodies required for early Drosophila development. J. Cell Biol. 174: 349-58.

Law, L.M.J., Ilkow, C.S., Tzeng, W.P., Rawluk, M., Stuart, D., Frey, T.K. and Hobman, T.C. (2006) Analyses of phosphorylation events in the Rubella virus capsid protein: Role in early replication events. J.Virol. 80:6917-6925.

Law, L.M.J., Ilkow, C.S., Tzeng, W.P., Rawluk, M., Stuart, D., Frey, T.K. and Hobman, T.C. (2006) Analyses of phosphorylation events in the Rubella virus capsid protein: Role in early replication events. J.Virol. 80:6917-6

Law, L.M.J., Ilkow, C.S., Tzeng, W.P., Rawluk, M., Stuart, D., Frey, T.K. and Hobman, T.C. (2006) Analyses of phosphorylation events in the Rubella virus capsid protein: Role in early replication events. J.Virol. 80:6917-6925.


Graduate Students
Shangmei Hou
Joaquin Lopez
Colleen Reid 
Yang Wang (Co-supervised with Dr. Paul LaPointe) 
Steven Willows 
 
Postdoctoral Fellows
Dr. Anil Kumar Victoria Ansalem
Dr. Zaikun Xu
Dr. JaeHwan You
 
Technicians
Valeria Mancinelli
Eileen Reklow
 
Lab Assistant
Anh Dang