Stephen Gould, Ph.D.

Professor of Biological Chemistry

Contact Information

Room 409, Physiology Building
410-955-3424; 410-955-3085
410-955-0215 (Fax)
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Research Interests

Exosome Exchange
Animal cells possess a pathway of intercellular vesicle traffic. This pathway, exosome exchange, involves the release of small (50-100 nm diameter) single-membrane bound vesicles and their subsequent fusion with neighboring cells. The consequence of this pathway is the delivery of membrane lipids and both membrane and cytosolic proteins from one cell to another, a process that has obvious implications for cell-cell communication. Exosome exchange plays critical roles in several physiological processes, including germ cell development, interactions between antigen presenting cells and lymphocytes, and morphogenesis. My primary interest in the exosome exchange pathway is to understand the molecular mechanisms that are involved in generating exosomal vesicles, releasing them from the cell, their attachment to neighboring cells, and the subsequent fusion between the exosome membrane and the target cell membrane. Current studies are directed at testing whether exosome formation requires the class E VPS proteins (a group of 20 proteins that involved in generating ‘reverse’ oriented vesicles at endosomal membranes) and factors that have been implicated in the fusion of late endosomes with the plasma membrane (Rab27 proteins, their effectors (Slp1, etc.), myosin V, etc.).
Virology
We recently proposed the ‘Trojan exosome hypothesis’ (Gould et al., 2003, PNAS 100:10592-7). This hypothesis, which is supported by a wide range of empirical evidence, states that retroviruses exploit exosome exchange for (i) the synthesis of retroviral particles, and (ii) a low-efficiency pathway of horizontal transfer that does not depend on retroviral proteins. This hypothesis reconciles the current model of retrovirus-directed transmission with the unique host lipids and host proteins in retroviral particles, the host cell proteins present in retroviral particles, the complex cell biology of retroviral release, the ability of retroviruses to infect cells that lack their receptor, and the horizontal transmission of Env-deleted retroviruses. HIV is a retrovirus and HIV infection causes Acquired Immune Deficiency Syndrome (AIDS), a progressive, lethal condition associated with the loss of immunity to infectious agents and cancers. The HIV pandemic has claimed 20 million lives, brought entire societies to the brink of social, economic and political collapse, and continues to spread through human populations at an accelerating rate. Not surprisingly, testing the Trojan exosome hypothesis is my highest research priority.
Peroxisome Biogenesis
My longest running research projects involve studies of peroxisomes, a different type of organelle that exists in the cytoplasm of all eukaryotic cells. Current research efforts on peroxisome biology span the topics of peroxisomal protein import, lipid import, peroxisome division, and peroxisome-associated diseases.

Selected Publications

  • South S and Gould SJ. Peroxisome synthesis in the absence of pre-existing peroxisomes. J Cell Biol 144:255-266, 1999.
  • Geraughty MT, Bassett DE Jr., Morrell JC, Bai J, Gatto G, Geisbrecht BV, Hieter P and Gould SJ. Detecting patterns of protein distribution and gene expression in silico. Proc Natl Acad Sci USA 96:2937-2942, 1999.
  • Chang CC, Warren DS, Sacksteder KA and Gould SJ. PEX12 interacts with PWX5 and PEX10 and acts downstream of receptor docking in peroxisomal matrix protein import. J Cell Biol 147:761-774, 1999.
  • Sacksteder KA, Jones JM, South S, Li X and Gould SJ. PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis. J Cell Biol 148:931-944, 2000.
  • Gatto, G., Geisbrecht, B. V., Gould, S. J., and Berg, J. (2000) Peroxisomal targeting signal-1 recognition by the TPR domains of human PEX5. Nat. Struct. Biol. 7, 1091-1095.
  • Jones, J. M., Morrell, J. C., and Gould, S. J. (2001) Multiple distinct targeting signals in integral peroxisomal membrane proteins. J. Cell Biol. 153, 1141-1150.
  • South, S.T., Baumgart, E., and Gould, S. J. (2001). Inactivation of the endoplasmic reticulum protein translocation factor, Sec61p, or its homolog, Ssh1p, does not affect peroxisome biogenesis. Proc. Natl. Acad. Sci USA. 98, 12027-12031.
  • Li, X., and Gould, S. J. (2002) PEX11 promotes peroxisome division independently of peroxisome metabolism. J. Cell Biol. 156, 643-651.
  • Li, X., Baumgart, E., Morrell, J. C., Jimenez-Sanchez, G., Valle, D., and Gould, S. J. (2002) PEX11s-deficiency is lethal and impairs neuronal migration but does not abrogate peroxisome function. Mol. Cell. Biol. 22, 4358-4365.
  • Li X., Baumgart, E., Dong, G. X., Morrell, J. C., Jimenez-Sanchez, G., Valle, D., Smith, K. D., Gould, S. J. (2002) PEX11alpha is required for peroxisome proliferation in response to 4-phenylbutyrate but is dispensable for peroxisome proliferator-activated receptor alpha-mediated peroxisome proliferation. Mol. Cell Biol. 22, 8226-40.
  • Li, X. and Gould, S. J. (2003) The dynamin-like GTPase DLP1 is essential for peroxisome division and is recruited to peroxisomes in part by PEX11. J. Biol. Chem. 278, 17012-17020.
  • Nguyen, D. G., Booth, A., Gould, S. J., and Hildreth, J. E. (2003) Evidence that HIV budding in primary macrophages occurs through the exosome release pathway. J. Biol. Chem. In press.
  • Gould, S. J., and Collins, C. S. (2002) Peroxisomal protein import: is it really that complex? Nature Rev. Mol. Cell Biol. 3, 382-389.
  • Gould, S.J., Booth, A., and Hildreth, J. E. K. (2003) The Trojan exosome hypothesis. Proc. Natl. Acad. Sci. USA. 100, 10592-10597.
 
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