My lab is interested in how cell death and inflammation are regulated. We focus on three key families of molecules:
* The tumor necrosis factor super family (TNFSF) that regulates the immune system and inflammation.
* Ubiquitin E3 ligases that play an important role regulating signalling from the TNFSF and other critical immune regulators.
* RIP Kinases, which play an important role in effecting inflammation, apoptotic and necroptotic cell death.
My lab uses a wide array of approaches including biochemistry, cell biology, small molecules and genetics so that discoveries made at the molecular level can be transposed into physiological findings in vivo. Using this approach I hope we can make medically relevant discoveries that can be translated into human treatments.
Switzerland, University of Zurich, PhD
BA (Hons) Cantab
2015 Thomson Reuters Citation Award
2009 Excellence in Research Award, La Trobe University
2016 Principal Research Fellowship (Senior Research Fellowships held 2009-2015)
2016 NHMRC Project Grant (also 2015, 2014 (x2), 2013 (x2), 2012, 2010, 2009, 2007)
2013 Grant In Aid, Cancer Council Victoria (CIB)
2006 Victoria Neurotrauma Initiative Grant
Scientific Advisory Board, TetraLogic Pharmaceuticals
Scientific Advisory Council, Bio21 Cluster
Editorial Board, Cell Death & Differentiation
Editorial Board, Science Signalling
Consultant, CRC for Biomarker Translation
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, Moura NS, Beck DB, Gutierrez-Cruz G, Ombrello AK, Pinto-Patarroyo GP, Kueh AJ, Herold MJ, Hall C, Wang H, Chae JJ, Dmitrieva NI, McKenzie M, Light A, Barham BK, Jones A, Romeo TM, Zhou Q, Aksentijevich I, Mullikin JC, Gross AJ, Shum AK, Hawkins ED, Masters SL, Lenardo MJ, Boehm M, Rosenzweig SD, Pasparakis M, Voss AK, Gadina M, Kastner DL, Silke J. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature. 2019 Dec 11. doi: 10.1038/s41586-019-1828-5. PMID: 31827281
Jaco, I, Annibaldi, A, Lalaoui, N, Wilson, R, Tenev, T, Laurien, L, Kim, C, Jamal, K, Wicky John, S, Liccardi, G, Chau, D, Murphy, JM, Brumatti, G, Feltham, R, Pasparakis, M*, Silke, J*, Meier, P*. MK2 Phosphorylates RIPK1 to Prevent TNF-Induced Cell Death. 2017. Mol Cell 66, 698-710.e5, doi: 10.1016/j.molcel.2017.05.003. PMID: 28506461
Brumatti G, Ma C, Lalaoui N, Nguyen NY, Navarro M, Tanzer MC, Richmond J, Ghisi M, Salmon JM, Silke N, Pomilio G, Glaser SP, de Valle E, Gugasyan R, Gurthridge MA, Condon SM, Johnstone RW, Lock R, Salvesen G, Wei A, Vaux DL, Ekert PG & Silke J. The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. Sci Transl Med. 2016; 8: 339ra69. PMID: 27194727
Lalaoui N, Hänggi K, Brumatti G, Chau D, Nguyen NN, Vasilikos L, Spilgies LM, Heckmann DA, Ma C, Ghisi M, Salmon JM, Matthews GM, de Valle E, Moujalled DM, Menon MB, Spall SK, Glaser SP, Richmond J, Lock RB, Condon SM, Gugasyan R, Gaestel M, Guthridge M, Johnstone RW, Munoz L, Wei A, Ekert PG, Vaux DL, Wong WW & Silke J. Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics. Cancer Cell. 2016; 29: 145-158. PMID: 26859455
Nachbur U, Stafford CA, Bankovacki A, Zhan Y, Lindqvist LM, Fiil BK, Khakham Y, Ko HJ, Sandow JJ, Falk H, Holien JK, Chau D, Hildebrand J, Vince JE, Sharp PP, Webb AI, Jackman KA, Mühlen S, Kennedy CL, Lowes KN, Murphy JM, Gyrd-Hansen M, Parker MW, Hartland EL, Lew AM, Huang DC, Lessene G & Silke J. A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production. Nat Commun. 2015; 6: 6442. PMID: 25778803
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. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell. 2014 May 22;157(5):1175-88. PMID: 24813849
Newton K, Hildebrand JM, Shen Z, Rodriguez D, Alvarez-Diaz S, Petersen S, Shah S, Dugger DL, Huang C, Auwerx J, Vandenabeele P, Green DR, Ashkenazi A, Dixit VM, Kaiser WJ, Strasser A, Degterev A, Silke J. Is SIRT2 required for necroptosis? Nature. 2014 Feb 27;506(7489):E4-6. PMID: 24572428
Vince JE, Wong WW, Gentle I, Lawlor KE, Allam R, O’Reilly L, Mason K, Gross O, Ma S, Guarda G, Anderton H, Castillo R, Hacker G, Silke J, Tschopp J. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity. 2012 Feb 24;36(2):215-27. PMID: 22365665
Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA, Anderton H, Wong WW, Nachbur U, Gangoda L, Warnken U, Purcell AW, Silke J, Walczak H. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011 Mar 31;471(7340):591-6. PMID: 21455173
Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J. IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell. 2007 Nov 16;131(4):682-93. PMID: 18022363
We are taking several approaches to explore the best way that IAP antagonists can be used in the clinic to treat cancer. This is an area of intense research world-wide but we have unique advantages including:
Using these reagents we are looking for the cancer types most responsive to birinapant killing and novel drug combinations that can overcome the resistance of other cancer types.
Team members: Dr Gabriela Brumatti, Dr Najoua Lalaoui
Using laboratory models of psoriasis and systemic inflammation we have shown that genetic loss of the key necroptosis effectors RIPK3 and MLKL significantly attenuates many aspects of the disease.
Working with other divisions at the institute, we have discovered novel small molecular inhibitors of necroptosis which we are now testing in this and other disease models.
Team member: Dr Joanne Hildebrand
We have shown that IAPs and RIPK2 play an important role in regulating signalling from NOD receptors, essential intracellular receptors that detect and respond to bacterial products. We are exploring a small molecule approach to explore this pathway and with collaborators at the institute we have developed and characterised a new RIPK2 inhibitor.
This has a fascinating mode of action: it delays signalling events such as NF-κB activation by only an hour or less, but completely inhibits the production of inflammatory cytokines by this pathway. We are exploring this further with mass spectrometry approaches.
Team member: Dr Ueli Nachbur
cIAPs and RIPK1 play important roles in regulating the signalling outcome downstream of TNF/TNFR1 activation. We have a long-standing interest in understanding how they function in this role, using a combination of genetics, small molecule inhibitor and mass spectrometry approaches.
More recently we have expanded our purview of this fascinating signalling paradigm by exploring the role of other regulators of this pathway including the linear ubiquitin assembly complex comprising the proteins SHARPIN, HOIL-1 and HOIP.