Welcome to !

Professor Joe Trapani

Peter MacCallum Cancer Centre
St Andrew's Place, East Melbourne, Vic 3002
Email: Joe.Trapani@petermac.org
Tel: +61-3-9656-3726
Fax: +61-3-9656-1411

Granzymes are a family of homologous serine proteases secreted by cytotoxic T lymphocytes and natural killer cells, cells of the immune system that kill virus-infected and transformed cells. Granzymes are distinguished from one another by their various substrate specificities. We have investigated the biochemistry, molecular and cellular biology and biological functions of granzymes for many years, commencing with the first cloning of human granzyme B cDNA. We have made major contributions to the understanding of the apoptotic pathways induced by granzyme B (which cleaves after aspartic acid), the mechanism through which it synergises with the pore-forming protein perforin to gain access to the target cell cytosol, delineated granzyme B substrates such as Bid, caspase-3 and filamin, and characterised granzyme trafficking pathways, particularly into the target cell nucleus (with Dr. David Jans). We have also used granzyme A and B-deficient mice to demonstrate that considerable functional redundancy exists among the granzymes in terms of CTL-mediated tumor rejection. Together with Dr. Phil Bird (Monash), we defined the serpin PI-9 as the cognate inhibitor of granzyme B. We also cloned human granzyme H, expressed the recombinant protease, defined granzyme H as a chymase, and characterised its tissue distribution. The function of granzyme H is unknown and we remain interested in defining its biological role.
More recently, we have become interested in understanding how CTL protect themselves against the toxic effects of perforin, and with Jose Villadangos, we are testing the hypothesis that cathepsin B expressed on the surface of CTL can proteolytically inactivate perforin molecules that diffuse back to the CTL plasma membrane following degranulation.
Phil Bird, Monash: serpin/granzyme interations
David Jans, Monash: cell trafficking of granzymes and perforin
Arno Mullbacher, ANU: granzymes in viral apthology
Gillian Griffiths, Oxford: perforin structure and function
Mark Smyth: biology of CTL/NK cells
Tom Kay: auto-immune tissue damage in diabetes
José Villadangos: cathepsin B
Ricky Johnstone: apoptotic pathways

Trapani, J.A., Sutton, V.R., Thia, K.Y.T., Li, Y.Q., Froelich, C.J., Jans, D.A., Sandrin, M.S. and Browne, K.A.: A clathrin/dynamin- and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death. J. Cell Biol. 160: 223-233, 2003.

Sutton, V.R., Wowk, M.E., Cancilla, M. and Trapani, J.A.: Caspase activation by granzyme B is indirect, and caspase auto-processing requires the release of pro-apoptotic mitochondrial factors. Immunity 18: 319-329, 2003.

Smyth, M.J., Street, S.E.A and Trapani, J.A.: Granzymes A and B are not essential for rejection of cancer. J. Immunol. 171: 515-518, 2003.

Browne, K.A., Johnstone, R.J. Jans, D.A. and Trapani, J.A.: Filamin (280kDa actin-binding protein) is a caspase substrate, and is also cleaved directly by the cytotoxic T lymphocyte protease granzyme B during apoptosis. J. Biol. Chem. 275: 39262-39266, 2000.

Edwards, K.M., Kam, C-M., Powers, J. and Trapani, J.A.: The human cytotoxic T cell granule protease granzyme H has chymotrypsin-like (chymase) activity and is taken up into cytoplasmic vesicles reminiscent of granzyme B-containing endosomes. J. Biol. Chem. 274: 30468-30473, 1999.

Questions/suggestions? Please contact the Network Administrator.
Copyright © by International Protease Network All Right Reserved.