The Zika ThreatASM Acts to Counter Zika Virus Outbreak.
Professor Kirsten Sandvig has been studying protein toxins from plants and bacteria, both using the toxins as probes to discover and characterize intraccllular pathways and with the goal of exploiting these toxins in medicine. A number of protein toxins produced by bacteria and found in plants enter eukaryotic cells and inhibit protein synthesis enzymatically. These toxins include the bacterial toxins diphtheria toxin, Pseudomonas exotoxin A, and Shiga toxins, and plant toxins such as ricin, abrin, modeccin and viscumin. Although toxins can be a threat to human health, these molecules are valuable tools to discover and characterize cellular processes such as endocytosis and intracellular transport. Correct regulation of intracellular transport is essential for normal cell growth, and cancers are often associated with changes in molecules involved in intracellular sorting of growth factors and receptors. Importantly, the toxins can also be exploited in cancer diagnosis and therapy. After binding to cell surface receptors, toxins are endocytosed by different mechanisms (both clathrin-dependent and –independent routes). One group of toxins, such as diphteria toxin undergoes a conformational change when exposed to low endosomal pH and is then inserted into the membrane and translocated to the cytosol, whereas other toxins such as Shiga toxin are transported from endosomes retrogradely to the Golgi apparatus and then to the ER before translocation to the cytosol. Professor Sandvig has been studying the toxins as such; their cleavage and activation by cellular enzymes and their entry into the cytosol, and, importantly, they have been used to characterize the pathways involved in their entry. Relatively new data show that intracellular transport is regulated not only by protein complexes and kinases, but also by the membrane lipid composition. A more detailed description of Sandvigs work, a complete list of references and main discoveries can be found at the homepages of the group: http://www.rr-research.no/sandvig/, and since the group belongs to a new Centre of Excellence “Centre for Cancer Biomedicine”, information can also be found on http://www.cancerbiomed.net/.
A few selected references and discoveries (out of about 250 articles) from 1980-2010: Discovery that low pH is able to trigger translocation of diphtheria toxin across the membrane. This is associated with a conformational change in the molecule and induction of cation-selective channels (Sandvig and Olsnes, J.Cell Biol. 1980; Sandvig and Olsnes, J.Biol.Chem.1981). Further studies of requirements for translocation: J.Cell Physiol. 1984; J.Biol.Chem. 1986; J.Biol.Chem. 1994. The lipid-binding Shiga toxin can induce its entry from clathrin-coated pits (Sandvig et al., J.Cell Biol. 1989; Sandvig et al., J.Cell Biol. 1991). A number of studies of various toxins showing that there are different endocytic mechanisms involved in their uptake. Discovery of retrograde transport of Shiga toxin to the ER (Sandvig et al., Nature 1992; and further studies of requirement for this transport (Sandvig et al., J. Cell Biol. 1994; Mol. Biol. Cell 1996). Shiga toxin is activated by furin (Garred et al., J.Biol.Chem. 1995). Retrograde tranport of cholera to the ER (Sandvig et al., PNAS 1996) and the finding that cholera toxin is endocytosed by different mechanisms, including clathrin-dependent endocytosis (Torgersen et al., J.Cell Sci. 2001). A number of studies of endocytosis and retrograde transport of toxins in the period until 2010 (for instance: Lauvrak et al., J.Cell Sci. 2002, 2004; Skånland et al., Traffic 2007, Cell.Microbiol. 2009, PLoS ONE 2009, Wälchli et al., Cell. Signal. 2009, Raa et al., Traffic 2009, Pust et al. PLoS ONE, 2010).