Professor Phillip Bird

Deputy Head, Department of Biochemistry and Molecular Biology

Telephone: +61-3-9902 9365

Facsimile:   +61-3-9902 9500

Office:         Room 246, Building 77

Email:          phil.bird@med.monash.edu.au

Link to Research Page

Background

I received my PhD in E.coli molecular genetics from the University of Melbourne in 1984. I then spent three years in the USA as a Damon Runyon-Walter Winchell Cancer Foundation Fellow working with Professor Joe Sambrook (FRS) on eukaryotic protein trafficking, first at the Cold Spring Harbor Laboratory and then at the University of Texas in Dallas. On my return to Australia I worked at the Commonwealth Serum Laboratories on the cloning and characterizing of pathogen antigens, and then joined the Department of Medicine at Monash University to work on the molecular regulation of blood coagulation. During this time I discovered a new group of human intracellular protease inhibitors (serpins), and my current research interests are focused on the biology of these proteins and their target proteases. In 2000 I moved to the Department of Biochemistry and Molecular Biology to join a cluster of groups interested in proteases and inhibitors. This led to a successful NHMRC Program grant application in 2003 and 2007.

Research Directions: Serpins, granzymes, perforin and cell death

We have proposed that intracellular serpins protect their host cells against protease-induced damage and apoptosis. One human intracellular serpin, PI-9, is a specific granzyme B inhibitor (granzyme B is produced by immune cytotoxic cells, and induces apoptosis of virus-infected and cancer cells by activating caspases in the cytoplasm after it is delivered there by perforin). We have shown that PI-9 is produced in cytotoxic cells and protects against granzyme B - mediated apoptosis, and that upregulation of PI-9 occurs in certain cancers, suggesting that cancer cells may overproduce PI-9 to evade the immune system. To further understand the role of PI-9 we are studying its distribution and function within cytotoxic cells.

An understanding of the roles and importance of the intracellular serpins requires an understanding of their target proteases.  We also study granzyme B, the target of PI-9 and its relatives. How and when granzyme B is released from cytotoxic lymphocytes and enters target cells, and how perforin releases it into the cytoplasm, is under investigation. We have identified regions on granzyme B required for its entry into cells, and have shown that it has an extracellular matrix-remodelling function, suggesting that its role extends beyond initiating apoptosis in compromised cells. We are using phage display to probe granzyme substrate specificity, live cell imaging to study granzyme trafficking, knockout mouse models to study granzyme pathophysiological function, and X-ray crystallography to study granzyme structure (with Prof James Whisstock). Also with Prof Whisstock we are elucidating the workings of perforin through analysis of proteins with related structure.

Funding

Research in my laboratory is currently funded by grants from the National Health and Medical Research Council.

Honours and Postgraduate Students

I have projects available to students wishing to undertake Honours or PhD studies in the Department. Please contact me for further details and to arrange to visit the lab.

Selected Publications

1. Sun J, Bird CH, Sutton V, McDonald L, Coughlin PB, De Jong TA, Trapani JA and Bird PI (1996). A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes. J. Biol. Chem. 271, 27802-27809.
2. Bird CH, Sutton VR, Sun J, Hirst CE, Novak A, Kumar S, Trapani JA and Bird PI (1998). Selective regulation of apoptosis: the cytotoxic lymphocyte serpin PI-9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol. Cell. Biol. 18, 6387-6398.
3. Scott FL, Hirst CE, Sun J, Bird CH, Bottomley SP and Bird PI (1999). The intracellular serpin proteinase inhibitor 6 (PI-6) is expressed in monocytes and granulocytes and is a potent inhibitor of the azurophilic granule protease, cathepsin G. Blood 93, 2089-2097.
4. Bird CH, Blink EJ, Hirst CE, Buzza MS, Steele PM, Sun J, Jans DA and Bird PI (2001). Nucleocytoplasmic distribution of the ovalbumin serpin PI-9 requires a non-conventional nuclear import pathway and the export factor Crm1. Mol Cell Biol 21, 5396-5407.
5. Hirst CE, Buzza MS, Bird CH, Warren HS, Cameron PU, Zhang M, Ashton-Rickardt PG and Bird PI (2003). The intracellular granzyme B inhibitor PI-9 is upregulated during accessory cell maturation and effector cell degranulation, and its overexpression enhances CTL potency. J Immunol 170, 805-815.
6. Buzza MS, Zamurs L, Sun J, Bird CH, Smith AI, Trapani JA, Froelich CJ, Nice EC, and Bird PI. (2005). Extracellular matrix remodeling by human granzyme B via cleavage of vitronectin, fibronectin and laminin. J Biol Chem. 280, 23549-58
7. Bird CH, Sun J, Ung K, Karambalis D, Whisstock JC, Trapani JA and Bird PI. (2005). Cationic sites on granzyme B contribute to cytotoxicity by promoting its uptake into target cells. Mol Cell Biol 25, 7854-7867.
8. Kaiserman D and Bird PI (2005). Analysis of vertebrate genomes suggests a new mechanism of clade B serpin evolution. BMC Genomics 6, 167.
9. Buzza M, Hosking P, and Bird PI (2006). The granzyme B inhibitor, PI-9, is differentially expressed during placental development and up-regulated in hydatidiform moles. Placenta 27, 62-69.
10. Kaiserman D, Bird CH, Sun J, Matthews A, Ung K, Whisstock JC, Thompson PE, Trapani JA, and Bird PI (2006). The major human and mouse granzymes are structurally and functionally divergent. J Cell Biol 175, 619-630.
11. Rosado CJ, Buckle AM, Law RH, Butcher RE, Kan WT, Bird CH, Ung K, Browne KA, Baran K, Bashtannyk-Puhalovich TA, Faux NG, Wong W, Porter CJ, Pike RN, Ellisdon  AM, Pearce MC, Bottomley SP, Emsley J, Smith AI, Rossjohn J, Hartland EL, Voskoboinik I, Trapani JA, Bird PI, Dunstone MA, Whisstock JC (2007). A common fold mediates vertebrate defense and bacterial attack. Science 317, 1548-51.
12. Buzza MS, Dyson JM, Choi H, Gardiner EE, Andrews RK, Kaiserman D, Mitchell CA, Berndt MC, Dong J-F and Bird PI. (2008). Anti-hemostatic activity of human granzyme B mediated by cleavage of von Willebrand factor and fibrinogen. J Biol Chem 283, 22498-504
13. Kaiserman D, Buckle AM, Van Damme P, Irving JA, Law RH, Matthews AY, Bashtannyk-Puhalovich T, Langendorf C, Thompson P, Vandekerckhove J, Gevaert K, Whisstock JC, and Bird PI. (2009). Structure of granzyme C reveals an unusual mechanism of protease autoinhibition. Proc Natl Acad Sci U S A.106, 5587-92.