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About

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.

Publications

Selected publications from Prof John Silke

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

Lab research projects

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