- Role: Senior Research ScientistGroup: Regulation of Interferon and Innate Signalling
Dr Sadler investigates the functioning of our immune system. After completing his early research training in microbial genetics at the University of Canterbury and in virology at the University of Otago, he travelled to the US where he conducted postdoctoral research into host immune responses to microbial pathogens at the Lerner Research Institute. This work was focused around the major antiviral interferon response. In 2006, he came to Australia, where he took up a position as a Senior Research Fellow within Hudson Institute. Here, Dr Sadler investigates innate immune responses that regulate inflammation, with the aim of identifying strategies to limit immune-mediated pathologies and treat ensuing disease.
Dr Sadler’s research focuses on one of the major goals of immune therapy; to curb damaging inflammation, while retaining immune resistance to pathogens. He has made advances in our understanding of processes that regulate cell signalling to control inflammatory responses, by identifying mechanisms of activity of the protein kinase R (J Mol Cell Biol 2014 and Sci Rep 2017), control of sterile inflammation (Cell Res 2016) and induction of anti-inflammatory cytokines (J Biol Chem 2008), and has determined novel antiviral mechanisms (PLoS Pathog 2009). He also identified a mechanism by which the innate immune response modulates the cell cytoskeleton to inhibit infectious virus entering the cell (Immunity 2012). This led to a second discovery with colleagues, demonstrating that control of the cytoskeleton regulates metastatic disease (Cancer Res 2013). He identified that post-translational modification of another component of the interferon response, the promyelocytic leukaemia zinc finger protein, is of critical importance in maintaining physiological balance in response to infection (Nat Commun 2015 and PNAS 2015). This report followed on from an earlier discovery (Immunity 2009) showing that the same transcription factor is critical for the antiviral response. He identified that another interferon-regulated factor, the melanoma differentiation-associated protein 5, alters the risk of developing the autoimmune condition, type I diabetes (EMBO J 2017).
His current research investigates how these factors control gene expression and cell signalling events during the immune response and which together detect stress, transduce cell signals and induce gene responses that control inflammation. Through these three molecules, Dr Sadler investigates a progression of immune pathologies from the initial responses to infection, through the development of persistent inflammatory conditions (colitis), to established chronic autoimmune diseases (type I diabetes and lupus).
- Treating infection-induced immune pathogenesis
- Evaluating interferon therapy against colitis
- Determining innate immune responses that induce type I diabetes
- Targeting cytokine signalling in systemic lupus erythematosus
Davidson S, Yu C-H, Steiner A, Ebstein F, Baker PJ, Jarur-Chamy V, Hrovat Schaale K, Laohamonthonkul P, Kong K, Calleja DJ, Harapas CR, Balka KR, Mitchell J, Jackson JT, Geoghegan ND, Moghaddas F, Rogers KL, Mayer-Barber KD, De Jesus AA, De Nardo D, Kile BT, Sadler AJ, Poli MC, Krüger E, Goldbach Mansky R, Masters SL (2022) Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24. Sci Immunol 7(68):eabi6763.
Szczepny A, Carey K, McKenzie L, Jayasekara WSN, Rossello F, Gonzalez-Rajal A, McCaw AS, Popovski D, Wang D, Sadler AJ, Mahar A, Russell PA, Wright G, McCloy RA, Garama DJ, Gough DJ, Baylin SB, Burgess A, Cain JE, Watkins DN (2018) The tumor suppressor Hic1 maintains chromosomal stability independent of Tp53. Oncogene 37(14):1939-1948.
Dou Y, Yim HCH, Kirkwood CD, Williams BRG, Sadler AJ (2017) The innate immune receptor MDA5 limits rotavirus infection but promotes cell death and pancreatic inflammation. EMBO J 36:2742-2757.
Wang D, de Weerd NA, Willard B, Polekhina G, Williams BRG, Sadler AJ (2017) Auto-phosphorylation represses protein kinase R activity. Sci Rep 7:44340.
Yim HCH, Wang D, Yu L, White CL, Faber PW, Williams BRG, Sadler AJ (2016) The kinase activity of PKR represses inflammasome activity. Cell Res 26:367-379.
Sadler AJ, Rossello FJ, Yu L, Deane JA, Yuan X, Wang D, Irving AT, Kaparakis-Liaskos M, Gantier MP, Ying H, Yim HCH, Hartland EL, Notini AJ, de Boer S, White SJ, Mansell A, Liu JP, Watkins DN, Gerondakis S, Williams BRG, Xu D (2015) The BTB-ZF transcriptional regulator PLZF modifies chromatin to restrain inflammatory signaling programs. Proc Natl Acad Sci USA 112:1535-1540.
Sadler AJ, Suliman BA, Yu L, Yuan X, Wang D, Irving AT, Sarvestani ST, Banerjee A, Mansell AS, Liu JP, Gerondakis S, Williams BR, Xu D (2015) The acetyltransferase HAT1 moderates the NF-kB response by regulating the transcription factor PLZF. Nat Commun 6:6795.
Liu MS, Wang D, Morimoto H, Yim HCH, Irving AT, Williams BRG, Sadler AJ (2014) Molecular dynamics reveal a novel kinase-substrate interface that regulates protein translation. J Mol Cell Biol 6:473-485.
Yuan X, Yu L, Li J, Xie G, Rong T, Zhang L, Chen J, Meng Q, Irving AT, Wang D, Williams ED, Liu JP, Sadler AJ, Williams BRG, Shen L, Xu D (2013) ATF3 suppresses metastasis of bladder cancer by regulating gelsolin-mediated remodeling of the actin cytoskeleton. Cancer Res 73:3625-3637.
Irving AT, Wang D, Vasilevski O, Latchoumanin O, Kozer N, Clayton AH, Szczepny A, Morimoto H, Xu D, Williams BRG, Sadler AJ (2012) Regulation of actin dynamics by protein kinase R control of gelsolin enforces basal innate immune defense. Immunity 36:795-806.
Sadler AJ, Latchoumanin O, Hawkes D, Mak J, Williams BRG (2009) An antiviral response directed by PKR phosphorylation of the RNA helicase A. PLoS Pathog 5:e1000311.
Xu D, Holko M, Sadler AJ, Scott B, Higashiyama S, Berkofsky-Fessler W, McConnell MJ, Pandolfi PP, Licht JD, Williams BRG (2009) Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity. Immunity 30:802-816.
Chakrabarti A, Sadler AJ, Kar N, Young HA, Silverman RH, Williams BRG (2008) Protein kinase R-dependent regulation of interleukin-10 in response to double-stranded RNA. J Biol Chem 283:25132-25139.
Sadler AJ, Williams BRG (2008) Interferon-inducible antiviral effectors. Nat Rev Immunol 8:559-568.