Defining regulators of cell death and inflammasome activation

Defining regulators of cell death and inflammasome activation is a Research Project for the Cell Death and Inflammatory Signalling Research Group, under the Centre for Innate Immunity and Infectious Diseases.

Project Leaders

Pattern recognition receptors, including Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are key components of the innate immune response. They sense microbial, host-derived and environmental danger molecules, and induce inflammatory signalling responses, via inflammasomes and other molecular complexes. We recently defined how deficiency in the cell death inhibitory protein XIAP sensitises innate immune cells to TLR-induced NLRP3 inflammasome activation (Lawlor KE et al. Nature Comms 2015, Lawlor KE* et al. Cell Reports 2017). Moreover, mutation of other cell death regulatory machinery drives hyperinflammation (Lalaoui N et al. 2020 Nature, Rickard JA et al. Elife 2014). The aim of this project is to further define molecules, like XIAP, that regulate this alternative inflammasome pathway. This project offers the opportunity to be trained in a variety of techniques, including cell culture, Western blotting/immunoprecipitation, proteomics, overexpression/CRISPR Cas9 gene editing, flow cytometry, ELISA and qPCR.

Collaborators: Paul Hertzog (Hudson Institute), James Vince, John Silke, Najoua Lalaoui (WEHI), Monica Yabal (Munich)

Selected publications

  • Lalaoui N*†, Boyden SE*†, Oda H, Wood GM, Stone DL, Chau D, Liu L, Stoffels M, Kratina T, Lawlor KE, Zaal KJM, Hoffmann PM, Etemadi N, Shield-Artin K, Biben C, Tsai WL, Blake MD, Kuehn HS, Yang D, Anderton H, Silke N, Wachsmuth L, Zheng L, Sampaio Mauora N, Beck DB, Guiterrez-Cruz G, Ombrello AK, Pinto-Patarroyo GP, Kueh AJ, Herold MJ, Hall C, Wang H, Chae JJ, Dimtrieva NI, McKenzie M, Light A, Barham BK, Jones A, Romeo TM, Zhou Q, Aksentijevich I, Mullikin JC, Gross AJ, Shum AK, Hawkins ED, Masters S, Lenardo MJ, Boehm M, Rosenzweig SD, Pasparakis M, Voss AK, Gadina M, Kastner DL#†, Silke J#†. (2020) Mutations that prevent caspase-8 cleavage of RIPK1 cause inflammation in humans and mouse. Nature 577:103-108

  • Speir M, Nowell CJ, Chen AA, O’Donnell JA, Shamie I, Lakin PR, D’Cruz AA, Braun RO, Babon JJ, Lewis RS, Bliss-Moreau M, Shlomovitz I, Wang S, Cengia LH, Stoica AI, Hakem R, Kelliher MA, O’Reilly LA, Patsiouras H, Lawlor KE, Weller E, Lewis NE, Roberts AW, Gerlic M, Croker BA (2020) Ptpn6 inhibits caspase-8 and Ripk3/Mlkl-dependent inflammation. Nature Immunology 21:54-64

  • 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

  • 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

  • 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

  • Rickard JA, Anderton H, Etemadi N, Nachbur U, Darding M, Lalaoui N, Lawlor KE, Vanyai H, Hall C, Bankovacki A, Gangoda L, Wong WW, Corbin J, Huang C, Mocarski ES, Murphy JM, Alexander WS, Voss AK, Vaux DL, Kaiser WJ, Silke J (2014) TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice. ELife 3: e03464

  • Rickard JA*, O’Donnell JA*, Evans JM*, Lalaoui N, Poh AR, Rogers T, Vince JE, Lawlor KE, Ninnis RL, Anderton H, Hall C, Spall SK, Phesse TJ, Abud HE, Cengia LH, Corbin J, Mifsud S, Di Rago L, Metcalf D, Ernst M, Dewson G, Roberts AW, Alexander WS, Murphy JM, Ekert PG, Masters SL, Vaux DL, Croker BA‡†., Gerlic M‡†., Silke J‡† (2014) RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157(5):1175-1188