Telephone: +61-3-9902 9365
Facsimile: +61-3-9902 9500
Office: Room 246, Building 77
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). In 2000 I moved my research group to the Department of Biochemistry and Molecular Biology to join other teams interested in proteases and inhibitors. This led to successful NHMRC Program grant applications in 2003 and 2007.
Research Directions: Serpins, granzymes, perforin and cell death
My group first proposed that intracellular serpins protect their host cells against protease-induced damage and apoptosis. We found that one human intracellular serpin, SERPINB9, is a specific granzyme B inhibitor. (Granzyme B is a protease produced by cytotoxic lymphocytes that kills virus-infected and cancer cells after it is delivered into the cytoplasm by the pore-forming protein, perforin.) SERPINB9 is produced within cytotoxic lymphocytes and protects them against their own granzyme B. Mice lacking this serpin fail to mount an effective immune response because their T cells are destroyed by their own uncontrolled granzyme B. In another example, mice lacking the related serpin, SERPINB6, are deaf because the inner ear degenerates due to loss of control of an as yet unidentified protease. Humans with mutations in SERPINB6 are also deaf.
Understanding the roles and importance of the intracellular serpins requires understanding of their target proteases. Thus we are studying how and when granzyme B is released from cytotoxic lymphocytes and enters target cells, and how perforin releases it into the cytoplasm. We have identified regions on granzyme B required for its entry into cells, and have recently shown that it has an additional extracellular matrix-remodelling function that assists lymphocytes to move into tissue from the bloodstream. We are also developing new ways to study perforin assembly on membranes using biophysical techniques.
Perforin is a member of the membrane attack complex / perforin (MACPF) family, which also includes well-known complement proteins in the immune system. These have evolved from an ancient protein called MPEG1. Interestingly, there are five less-studied members of the family (three BRINPs and two ASTNs), all expressed in the nervous system. We have generated mice lacking BRINPs and are examining the consequences for brain development and function.
Research in my laboratory is currently funded by grants from the National Health and Medical Research Council, and the Australian 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- 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.
- Kaiserman D and Bird PI (2005). Analysis of vertebrate genomes suggests a new mechanism of clade B serpin evolution. BMC Genomics 6, 167.
- 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.
- 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.
- 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.
- 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
- 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.
- Law RHP, Lukoyanova N, Voskoboinik I, Caradoc-Davies TT, Baran K, Verschoor S, Browne KA, Ciccone A, Kuiper MJ, Bird PI, Trapani JA, Saibil HR & Whisstock JC (2010). The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 468, 447-451. doi:10.1038/nature09518
- D'Angelo ME, Dunstone MA, Whisstock JC, Trapani JA, & Bird PI. (2012). Perforin evolved from a gene duplication of MPEG1, followed by a complex pattern of gene gain and loss within Euteleostomi. BMC Evolutionary Biology, 12, 59. doi:10.1186/1471-2148-12-59
- Rizzitelli A, Meuter S, Ramos JV, Bird CH, Mintern JD, Mangan MSJ, Villadangos J and Bird PI. (2012). Serpinb9 (Spi6)-deficient mice are impaired in dendritic cell-mediated antigen cross-presentation. Immunology and Cell Biology, 90(9), 841-51. doi:10.1038/icb.2012.29
- Tan J, Kaiserman D and Bird PI (2013). Absence of Serpinb6a causes sensorineural hearing loss with multiple histopathologies in the mouse inner ear Am J Pathol - in press.