Prof Sandra Nicholson, Lab Head | WEHI Researcher Profile

Q: SOCS proteins in Inflammation

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.

Q: Regulating anti-viral immunity

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.

Q: SPRY and SOCS box proteins in inflammation

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.

About

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.

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Selected publications from Prof Sandra Nicholson

Bidgood GM, Keating N, Guzman LM, Li K, Leong E, Kueh A, Babon JJ, Hockings C, Doggett K, Nicholson SE. The Ability of SOCS1 to Cross-Regulate GM-CSF Signaling is Dose Dependent. Journal of Interferon & Cytokine Research. 2025;45(2):10.1089/jir.2024.0140

Nicholson SE, Ahmed CM, Doggett K, Marasco D, Johnson HM. Editorial: SOCS: regulation of the immune system at a whole new level. Frontiers in Immunology. 2025;16:10.3389/fimmu.2025.1588549

Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, Stannard K, Zhang J-G, Teh 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. Author Correction: CIS is a potent checkpoint in NK cell–mediated tumor immunity. Nature Immunology. 2024;25(2):10.1038/s41590-023-01714-8

Guzman LGM, Hyland CD, Bidgood GM, Leong E, Shen Z, Goh W, Rautela J, Vince JE, Nicholson SE, Huntington ND. CD45 limits early Natural Killer cell development. Immunology and Cell Biology. 2024;102(1):10.1111/imcb.12701

Bidgood GM, Keating N, Doggett K, Nicholson SE. SOCS1 is a critical checkpoint in immune homeostasis, inflammation and tumor immunity. Frontiers in Immunology. 2024;15:10.3389/fimmu.2024.1419951

Linossi EM, Li K, Veggiani G, Tan C, Dehkhoda F, Hockings C, Calleja DJ, Keating N, Feltham R, Brooks AJ, Li SS, Sidhu SS, Babon JJ, Kershaw NJ, Nicholson SE. Author Correction: Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands. Nature Communications. 2023;14(1):10.1038/s41467-023-42706-4

Doggett K, Keating N, Dehkhoda F, Bidgood GM, Meza Guzman LG, Leong E, Kueh A, Nicola NA, Kershaw NJ, Babon JJ, Alexander WS, Nicholson SE. The SOCS1 KIR and SH2 domain are both required for suppression of cytokine signaling in vivo. Cytokine. 2023;165:10.1016/j.cyto.2023.156167

Kedzierski L, Tan AEQ, Foo IJH, Narayanan D, Moily N, McQuilten HA, Nicholson SE, Fazakerley JK. In Semliki Forest virus encephalitis, suppressor of cytokine signaling 4 (SOCS4) is an essential modulator of immune responses that mediates the balance between immunopathology and virus clearance. Immunology and Cell Biology. 2023;101(4):10.1111/imcb.12625

Chen H, Nguyen NH, Magtoto CM, Cobbold SA, Bidgood GM, Guzman LGM, Richardson LW, Corbin J, Au AE, Lechtenberg BC, Feltham R, Sutherland KD, Grohmann C, Nicholson SE, Sleebs BE. Design and characterization of a heterobifunctional degrader of KEAP1. Redox Biology. 2023;59:10.1016/j.redox.2022.102552

Zhang S, Rautela J, Bediaga NG, Kolesnik TB, You Y, Nie J, Dagley LF, Bedo J, Wang H, Sun L, Sutherland R, Surgenor E, Iannarella N, Allan R, Souza-Fonseca-Guimaraes F, Xie Y, Wang Q, Zhang Y, Xu Y, Nutt SL, Lew AM, Huntington ND, Nicholson SE, Chopin M, Zhan Y. CIS controls the functional polarization of GM-CSF-derived macrophages. Cellular & Molecular Immunology. 2023;20(1):10.1038/s41423-022-00957-z

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SOCS proteins in Inflammation

Regulating anti-viral immunity

SPRY and SOCS box proteins in inflammation

Prof Sandra Nicholson

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