|Leonard C. Norkin
Professor of Microbiology, University of Massachusetts
Ph.D.: Columbia University
Virus Entry through Caveolae: Transmembrane Signaling
A virus initiates infection by binding to its specific receptor on the surface of a susceptible cell. Many viruses then enter the cell by receptor-mediated endocytosis, in which the virus-receptor complexes concentrate in clathrin-coated pits which constitutively invaginate to form intracellular vesicles.
Our research showed that entry of the tumor virus simian virus 40 (SV40) differs in important ways from the usual coated pit-mediated process. First, SV40 enters cells through non-coated plasma membrane invaginations called caveolae. Second, SV40 entry is induced by a signal that the virus transmits from the cell surface. Unlike coated pits, the functions of caveolae are not yet clear, although they have been implicated in both endocytosis and transmembrane signaling.
A major goal of our research is to determine how the SV40-induced transmembrane signal actually promotes SV40 entry through caveolae. Our current work suggests that the signal enables SV40 to enter preformed empty caveolae. However, we need to identify the mediators and membrane targets of the signal. Also, we need to determine whether the signal also promotes downstream events in the entry pathway, such as budding of the caveolae and docking with intracellular targets. This work is important because it is characterizing a previously unknown virus entry pathway and because it focuses on the poorly understood cellular mechanism of endocytosis through non-coated vesicles.
Norkin, L. C., H. A. Anderson, S. A. Wolfrom and A. Oppenheim (2002). "Caveolar endocytosis of simian virus 40 is followed by brefeldin A-sensitive transport to the endoplasmic reticulum, where the virus disassembles." J Virol 76(10): 5156-66.
Norkin, L. C. (2001). "Caveolae in the uptake and targeting of infectious agents and secreted toxins." Adv Drug Deliv Rev 49(3): 301-15.
Norkin, L. C., S. A. Wolfrom and E. S. Stuart (2001). "Association of caveolin with Chlamydia trachomatis inclusions at early and late stages of infection." Exp Cell Res 266(2): 229-38.
Norkin, L. C. (1999). "Simian virus 40 infection via MHC class I molecules and caveolae." Immunol Rev 168: 13-22.
Chen, Y. and L. C. Norkin (1999). "Extracellular simian virus 40 transmits a signal that promotes virus enclosure within caveolae." Exp Cell Res 246(1): 83-90.
Anderson, H. A., Y. Chen and L. C. Norkin (1998). "MHC class I molecules are enriched in caveolae but do not enter with simian virus 40." J Gen Virol 79 ( Pt 6): 1469-77.
Anderson, H.A., Chen, Y. and Norkin, L.C. (1998) MHC class I molecules are enriched in caveolae but do not mediate simian virus 40 entry or internalize spontaneously. J. Gen. Virol. 79, 1469-1477.
Anderson, H.A., Chen, Y. and Norkin, L.C. (1996) Bound simian virus 40 translocates to caveolin-enriched membrane domains and its entry is inhibited by drugs that selectively disrupt caveolae. Mol. Biol. Cell. 7, 1825-1834.
Dangoria, N.S., Breau, W.C., Cishek, D.M., Anderson, H.A. and Norkin, L.C. (1996) Extracellular simian virus 40 induces an ERK/MAPK-independent signaling pathway that activates primary response genes and promotes virus entry. J. Gen. Virol. 77, 2173-2182.
Norkin, L.C. and Anderson, H.A. (1996) Multiple stages of virus-receptor interactions as shown by simian virus 40. Adv. Exp. Biol. Med. 408, 159-167.
Norkin, L.C. (1995) Virus receptors: implications for pathogenesis and the design of antiviral agents. Clin. Microbiol. Rev. 8, 293-315.