Identifying mitochondrial factors that activate inflammatory signalling is a Research Project for the Cell Death and Inflammatory Signalling Research Group, under the Centre for Innate Immunity and Infectious Diseases.
Mitochondrial (“intrinsic” BCL-2 family regulated) apoptosis has long been thought to be immunologically silent. However, using small molecule inhibitors of pro-survival BCL-2 family members, we have recently discovered that mitochondrial apoptosis can induce a cascade of events that culminate in activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and pro-inflammatory cytokine, Interleukin-1beta (Vince JE Cell Reports 2018). In this project we will further characterise this pathway and test whether its activation alters cancer progression in vivo. This project will use our novel gene knockout macrophages and specific targeted drugs, as well as a range of cell biology and biochemical/molecular approaches (e.g. inflammasome/cell death assays, ELISA, Western blotting, CRISPR Cas9 gene editing screens, proteomics).
Collaborators: Gabriela Brumatti, James Vince (WEHI)
Vince JE*, De Nardo D, Gao W, Vince AJ, Hall C, McArthur K, Simpson D, Vijayaraj S, Lindqvist LM, Bouillet P, Rizzacasa M, Man SM, Silke J, Masters SL, Lessene G, Huang DCS, Gray DHD, Kile BT, Shao F, Lawlor KE* (2018) The Mitochondrial Apoptotic Effectors BAX/BAK Activate Caspase-3 and -7 to Trigger NLRP3 Inflammasome and Caspase-8 Driven IL-1 Activation. Cell Reports 25(9):2339-2353
Allam R*, Lawlor KE*, Yu EC, Mildenhall AL, Moujalled DM, Lewis RS, Ke F, Mason KD, White MJ, Stacey KJ, Strasser A, Alexander W, Kile BT, Vaux DL, Vince JE (2014) Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Reports 15(9):982-990