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Gary Thomas received his Ph.D. in Biochemistry from the Biozentrum at the University of Basel, Switzerland, in 1984 after earning his B.S. at Boise State University. He did his postdoctoral fellowship at the University of Oregon and at the Vollum Institute. Thomas has been a faculty member in the Vollum since 1987 and was promoted to senior scientist in 1999. He is also director of the Program in Molecular and Cellular Biosciences and a professor of Cell and Developmental Biology in the School of Medicine. Research InterestsThe Thomas lab studies the cellular machinery that directs the sorting of membrane proteins between secretory pathway compartments and examines how this machinery controls cellular homeostasis and disease. The endoplasmic reticulum (ER) functions with the Golgi to control the production of secretory proteins and with mitochondria to regulate cellular homeostasis and activation of cell death pathways. Little is known about the molecular machinery that integrates the ER-Golgi and ER-mitochondria axes. Thomas and his colleagues have identified the PACS family of sorting proteins, which control key sorting steps between the various secretory pathway compartments and mitochondria. One member of this family, PACS-1, localizes several membrane proteins, including processing enzymes, receptors, transporters and snare proteins, to the trans-Golgi network (TGN) by binding to phosphorylatable acidic cluster motifs in their cytoplasmic domains and connecting them to clathrin adaptors. PACS-1 itself contains a phosphorylatable acidic cluster motif that is part of an autoregulatory domain that controls its sorting activity. Thomas and his colleagues are determining how signaling pathways converge on PACS-1 to control protein traffic in the secretory pathway. The identification of the PACS-1 has provided new insights into the molecular basis of viral pathogenesis. For example, the lab has shown that HIV-1 Nef usurps the PACS-1 sorting pathway to downregulate cell surface MHC-I molecules via a phosphatidylinositol-3 kinase (PI3K)-mediated ARF6 sorting pathway, enabling the virus to evade the immune surveillance system. Exactly how PACS-1 and Nef combine to activate PI3K and ARF6 is currently being investigated. PACS-1 is also required to localize many herpesvirus envelope glycoproteins to the TGN, the putative location of viral envelopment. Disruption of PACS-1 sorting activity reduces virus production, suggesting that PACS-1 is a key cellular factor that controls herpesvirus assembly. Thomas and his colleagues have recently determined that the second member of the PACS family, PACS-2, controls the ER-mitochondria axis and apoptosis. PACS-2 localizes several membrane proteins, including chaperones and ion channels, to the ER by connecting them to COPI. PACS-2 is also essential for juxtaposing rod-shaped mitochondria with the ER, which maintains the oxidative ER microenvironment and calcium stores. Moreover, in response to cell-death inducers, PACS-2 initiates apoptosis by translocating the proapoptotic protein Bid to mitochondria. Thus, the identification of the PACS family of sorting proteins has provided new insights into the regulation of protein traffic, the molecular basis of viral pathogenesis, and the control of cell fate. Selected PublicationsKöttgen, M, et al. (2005) Trafficking of TRPP2 by PACS proteins represents a novel mechanism of ion channel regulation. EMBO J. 24:705-716. Simmen, T, et al. (2005) PACS-2 Controls ER-Mitochondria Communication and Bid-mediated Apoptosis. EMBO J. 24:717-729. Scott, G.K., Gu, F., Crump, C.M., Thomas, L., Wan, L., Xiang, Y., and Thomas, G. (2003) The phosphorylation state of an autoregulatory domain controls PACS-1-directed protein traffic. EMBO J. 22:6234-6244. Crump, C.M., Hung, C.H., Thomas, L., Wan, L., and Thomas, G. (2003) Role of PACS-1 in trafficking of human cytomegalovirus glycoprotein B and virus production. J. Virology 77:11105-11113. Blagoveshchenskaya, A.D., Thomas, L., Feliciangeli, S.F., Hung, C.H., and Thomas, G. (2002) HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway. Cell 111:853-866. Thomas, G. (2002) Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nature Rev. Mol. Cell Biol. 3:753-766.
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