Role of Cell Death and pore forming proteins in Type 2 Diabetes

Role of Cell Death and pore forming proteins in Type 2 Diabetes is a Research Project for the Cell Death and Inflammatory Signalling Research Group, under the Centre for Innate Immunity and Infectious Diseases.

Project Leaders

Dietary danger molecules, such as the saturated fatty acid palmitate, trigger the activation of the pro-inflammatory cytokine, interleukin-1β (IL-1β), via NLRP3 inflammasome activation. Based on our past work (Lawlor KE et al. Nature Commun 2015 6:282) we are examining the contribution of extrinsic apoptotic caspase-8 and necroptotic MLKL activity to pathogenic NLRP3 inflammasome activation and Type 2 Diabetes development. Gasdermins (GSDMs) are a family of membrane pore-forming proteins that have recently been defined as proteolytic caspase substrates that induce an inflammatory form of lytic cell death called pyroptosis (Kayagaki N et al. Nature 2015 526:666; Orning P et al. Science 2018 362:1064, Wang Y et al. Nature 2017 547:99). The aim of this project is to define how pyroptotic cell death contributes to NLRP3 inflammasome activation and/or DAMP release to worsen obesity-induced Type 2 Diabetes This project offers the opportunity to be trained in a variety of techniques, including cell culture, Western blotting, inflammasome/cell death assays, ELISA, qPCR, tissue analysis – histology, flow cytometry, serum/liver/adipose metabolic assays, Type 2 diabetes preclinical models.

Collaborators: James Murphy, Seth Masters, James Vince (WEHI), Andrew Murphy (Baker Heart and Diabetes Institute)

Selected publications

  • Conos SA, Chen KW, De Nardo D, Whitehead L, Hara H, Vaux DL, Nùñez G, Masters SL, Murphy JM, Schroder K, Lawlor KE*, Lindqvist LM*, Vince JE* (2017) Active MLKL triggers the NLRP3 inflammasome in a cell intrinsic manner. Proceedings of the National Academy of Sciences USA 114(6):E961-E969

  • Murphy AJ, Kraakman MJ, Kaummon HL, Dragoljevic D, Lee MK, Lawlor KE, Wentworth JM, Vasanthakumar A, Gerlic M, Whitehead LW, DiRago L, Cengia L, Lane RM, Metcalf D, Vince JE, Harrison LC, Kallies A, Kile BT, Croker BA, Febbraio MA, Masters SL (2016)  IL-18 production from the NLRP1 inflammasome prevents Obesity and Metabolic Syndrome. Cell Metabolism 23(1):155-164

  • Lawlor KE†, Khan N, Mildenhall A, Gerlic M, Croker BA, D’Cruz AA, Hall C, Spall S, Anderton H, Masters SL, Rashidi M, Wicks IP, Alexander WS, Mitsuuchi Y, Benetatos CA, Condon SM, Wong WW, Silke J*, Vaux DL* Vince JE*† (2015) RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nature Communications 6:6282

  • 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 * co-corresponding authors

  • Lawlor KE*, Feltham RL*, Yabal M*, Conos SA, Chen KW, Ziehe S, Graß C, Zhan Y, Nguyen TA, Hall C, Vince AJ, Chatfield SM, D’Silva DB, Pang KC, Schroder K, Silke J, Vaux DL, Jost PJ†, Vince JE†‡ (2017) XIAP Loss Triggers RIPK3 and Caspase-8-Driven IL-1 activation and Cell Death as a Consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation. Cell Reports 20(3):668-682. *,† equal contribution; ‡ co-corresponding authors

  • Conos SA, Chen KW, De Nardo D, Whitehead L, Hara H, Vaux DL, Nùñez G, Masters SL, Murphy JM, Schroder K, Lawlor KE*, Lindqvist LM*, Vince JE* (2017) Active MLKL triggers the NLRP3 inflammasome in a cell intrinsic manner. Proceedings of the National Academy of Sciences USA 114(6):E961-E969. *co-senior/corresponding authors

  • Lawlor KE*, Khan N, Mildenhall A, Gerlic M, Croker BA, D’Cruz AA, Hall C, Spall S, Anderton H, Masters SL, Rashidi M, Wicks IP, Alexander WS, Mitsuuchi Y, Benetatos CA, Condon SM, Wong WW, Silke J†, Vaux DL† Vince JE*† (2015) RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nature Communications 6:6282. *co-corresponding authors

  • 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. *co-first authors

  • Lawlor KE, van Nieuwenhuijze A, Parker KL, Drake SF, Campbell IK, Smith SD, Vince JE, Strasser A, Wicks IP (2013) Bcl-2 overexpression ameliorates immune complex-mediated arthritis by altering FcγRIIb expression and monocyte homeostasis. Journal of Leukocyte Biology 93(4):585-597.

  • Lawlor KE, Smith SD, van Nieuwenhuijze A, Huang DC, Wicks IP (2011) Evaluation of Bcl-2 antagonist ABT-737 in collagen-induced arthritis. Journal of Leukocyte Biology 90(4):819-829.