I am interested in how the body initiates an innate immune response to infectious pathogens and then maintains ‘helpful’, rather than ‘damaging’ inflammatory responses.
The SOCS proteins are classic negative regulators that act as a handbrake to limit the damage associated with excessive pro-inflammatory cytokine signalling. TRIM proteins are another important class of intracellular proteins which both positively and negatively regulate innate immune signalling.
Our research program aims to understand the molecular detail of SOCS and TRIM protein complexes and how these signalling complexes are regulated in inflammatory and infectious disease. We are taking an integrated multi-disciplinary approach, which utilises in vivo model systems, quantitative proteomics and structural biology.
Ultimately, I am interested in the connection between the deregulation of intracellular signalling and disease. Within this context, my research is focused on understanding how these protein families regulate innate immunity.
Australia, Monash University, BSc MSc
Australia, University of New South Wales, PhD
2008, Senior Research Fellowship SRFA, National Health and Medical Research Council
2004, RD Wright Biomedical Career Development Award, National Health and Medical Research Council
2001, Australian Postdoctoral Fellowship, Australian Research Council
2012, Program grant, National Health and Medical Research Council
2011, RO1, National Institutes of Health USA
2010, Project grant, National Health and Medical Research Council
2010, Program grant, National Health and Medical Research Council
2008, Project grant, National Health and Medical Research Council
Board director, Australian Society for Medical Research, 2004-2007
Convenor, 3rd Australian Health & Medical Research Congress (AH&MRC), Melbourne, 2006
Editorial Advisor, Biochemical Journal, 2006-present
Grant review panels, National Health and Medical Research Council, 2007-2010, 2012
Kedzierski L, Tate M, Hsu A C-Y, Kolesnik TB, Dagley L, Dong Z, Linossi E, Freeman S, Infusini G, Bird N, Chatfield SM, Belz, G, Webb A, Wark PAB, Nicola NA, Xu J, Kedzierska K, Hansbro PM, Nicholson SE. Suppressor of Cytokine Signaling (SOCS)5 ameliorates influenza infection via inhibition of EGFR-PI3K signaling. 2017 eLIFE doi:10.7554/eLife.20444 PMID: 28195529
Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, Stannard K, Zhang J-G, The C, Firth M, Ushiki T, Andoniou CE, Degli-Esposti MA, Sharp PP, Sanvitale CE, Infusini G, Liau NPD, Linossi EM, Burns CJ, Carotta S, Gray DHD, Seillet C, Hutchinson DS, Belz GT, Webb AI, Alexander WS, Li SS, Bullock AN, Babon JJ, Smyth MJ, Nicholson SE, Huntington ND. CIS is a potent checkpoint in NK cell-mediated tumour immunity. Joint senior author, Nature Immunology 2016 17, 816–824 PMID: 27213690
Kedzierski L, Linossi EM, Kolesnik TB, Day EB, Bird NL, Kile BT, Belz GT, Metcalf D, Nicola NA, Kedzierska K, Nicholson SE. Suppressor of cytokine signaling 4 (SOCS4) protects against severe cytokine storm and enhances viral clearance during influenza infection. PLoS Pathog. 2014 May;10(5):e1004134. PMID: 24809749.
D’Cruz AA, Kershaw NJ, Chiang JJ, Wang MK, Nicola NA, Babon JJ, Gack MU, Nicholson SE. Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling. Biochem J. 2013 Dec 1;456(2):231-40. PMID: 24015671.
Lewis RS, Kolesnik TB, Kuang Z, D’Cruz AA, Blewitt ME, Masters SL, Low A, Willson T, Norton RS, Nicholson SE. TLR regulation of SPSB1 controls inducible nitric oxide synthase induction. J Immunol. 2011 Oct 1;187(7):3798-805. PMID: 21876038.
Kuang Z, Lewis RS, Curtis JM, Zhan Y, Saunders BM, Babon JJ, Kolesnik TB, Low A, Masters SL, Willson TA, Kedzierski L, Yao S, Handman E, Norton RS, Nicholson SE. The SPRY domain-containing SOCS box protein SPSB2 targets iNOS for proteasomal degradation. J Cell Biol. 2010 Jul 12;190(1):129-41. PMID: 20603330.
Masters SL, Yao S, Willson TA, Zhang JG, Palmer KR, Smith BJ, Babon JJ, Nicola NA, Norton RS, Nicholson SE. The SPRY domain of SSB-2 adopts a novel fold that presents conserved Par-4-binding residues. Nat Struct Mol Biol. 2006 Jan;13(1):77-84. PMID: 16369487.
Babon JJ, McManus EJ, Yao S, DeSouza DP, Mielke LA, Sprigg NS, Willson TA, Hilton DJ, Nicola NA, Baca M, Nicholson SE, Norton RS. The structure of SOCS3 reveals the basis of the extended SH2 domain function and identifies an unstructured insertion that regulates stability. Mol Cell. 2006 Apr 21;22(2):205-16. PMID: 16630890.
Nicholson SE, De Souza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, Silva A, Asimakis M, Farley A, Nash AD, Metcalf D, Hilton DJ, Nicola NA, Baca M. Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6493-8. PMID: 10829066.
Nicholson SE, Willson TA, Farley A, Starr R, Zhang JG, Baca M, Alexander WS, Metcalf D, Hilton DJ, Nicola NA. Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J. 1999 Jan 15;18(2):375-85. PMID: 9889194.
Cytokine signalling is initiated through interaction with specific transmembrane receptor subunits. The subsequent receptor oligomerisation activates either an intrinsic kinase domain or the receptor associated JAK kinases, and the following cascade of intracellular phosphorylation and signal transduction culminates in an appropriate cellular response. This cascade requires exquisite cellular control, and loss of regulation can promote tumorigenesis and chronic inflammation. The expression of SOCS proteins can be induced by cytokine stimulation, and they serve to interfere with signalling not only from the inducing cytokine in a classic “negative-feedback” loop, but also to regulate signalling downstream of other cytokines.
Many TRIM (tripartite motif) proteins are involved in anti-viral defence, innate immunity and inflammation. The B30.2 or PRYSPRY domain is a modular protein interaction domain found in TRIM proteins including TRIM5alpha, which controls HIV infection, TRIM20, which is mutated in familial Mediterranean fever and TRIM25, which regulates the viral RNA sensor RIG-I. We are interested in understanding how the B30.2-containing TRIM proteins recognize their cellular targets, and particularly how TRIM25 interacts with and activates RIG-I. This may lead to the development of new drugs that can either decrease inflammation to prevent chronic disease, or trigger the innate immune system to fight infection.
The SPSB protein family is characterized by a central SPRY protein-interaction domain and a C-terminal SOCS box motif. The SOCS box motif recruits an E3 ubiquitin ligase complex, which polyubiquitinates target proteins, resulting in their proteasomal degradation. The number of proteins encoding SPRY domains now exceeds 74. These proteins are implicated in diverse biological processes including development and innate immunity.
We are interested in identifying potential binding partners for the SPSB proteins, and how the SPRY domain interacts with its target proteins. We have obtained detailed structural information on the binding interface between SPSB SPRY domains and the N-terminus of iNOS, and we are now interested in identifying lead compounds to disrupt this interaction.
Collaboration with Professor Ray Norton, Monash Institute of Pharmaceutical Sciences