Bird, Phil - Monash University - Department of Biochemistry and Molecular Biology

研究领域

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.

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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.