Edgington-Mitchell laboratory: Protease pathophysiology

• A/Prof Laura Edgington-Mitchell

  Head of Research Group

  laura.edgingtonmitchell@unimelb.edu.au
  + 61 3 903 54630

Research Overview

Proteases are enzymes that cleave peptide bonds in proteins, underpinning vital physiological processes that sustain life. Beyond their fundamental roles in digestion, protein turnover, and maintaining cellular homeostasis, proteases orchestrate highly regulated signalling pathways involved in programmed cell death, blood coagulation, hormone processing, antigen presentation, and cell migration. When protease activity is dysregulated, it contributes to the development and progression of diseases such as cancer, chronic inflammation, and neurodegenerative disorders.

The Protease Pathophysiology Laboratory takes a multidisciplinary approach to unravel how proteases shape health and disease. We harness innovative chemical tools to detect and inhibit the activation of diverse cysteine and serine proteases in vitro, in preclinical models of inflammation and cancer, and in clinical patient samples. By integrating chemical proteomics, we identify protease substrates and map their functional impact. Together, these strategies advance our understanding of protease biology and validate new opportunities to target proteases as biomarkers and therapeutic interventions.

Techniques:
- Protein Biochemistry
- Activity-based probe development and application
- Chemical Proteomics
- Microscopy
- Molecular Biology (CRISPR gene editing)

Staff

Alexander Ziegler, PhD Student

Stephanie Luedtke, PhD Student

Marc Khorey, Honours Student

Dr Florence Yek, Research Fellow

Collaborators

Associate Professor Nichollas Scott, University of Melbourne
Professor Hayley Newton, Monash University
Associate Professor Antoine Dufour, University of Calgary, Canada
Professor Brian L Schmidt, New York University, USA
Professor Nigel Bunnett, Columbia University, USA
Professor Matthew Bogyo, Stanford University, USA
Professor Keqiang Ye, SIAT, China

Funding

NHMRC Ideas Grant (2022-2025)

PdCCRS Young Investigator Award (2019-2020)

NHMRC Peter Doherty Early Career Fellowship (2015-2018)

Grimwade Research Fellowship (2018-2022)

ARC DECRA Fellowship (2019-2021)

Research Publications

A complete list of publications can be found at  http:scholar.google.com/citations?user=7julmp4AAAAJ&hl=en

1. Bird, L.E., Xu, B., Hobbs, A.D., Ziegler, A.R., Scott, N.E., Newton, P., Thomas, D.R., Edgington-Mitchell, L.E.*, Newton, H.J.* (2025) Coxiella burnetii manipulates the lysosomal protease cathepsin B to facilitate intracellular success. Nature Communications. 16:3844.

2. Xu, B.,* Mountford, S.J.,* Thompson, P.E., Edgington-Mitchell, L.E. (2024) Expanding the library of covalent cysteine cathepsin probes featuring sulfoxonium ylide electrophiles. ACS Omega 9:43940-43947.

3. Ziegler, A.R., Anderson, B.M., Latorre, R., McQuade, R.M., Dufour, A., Schmidt, B.L., Bunnett, N.W., Scott, N.E. Edgington-Mitchell, L.E. (2024) N-terminomics profiling of naïve and inflamed murine colon reveals proteolytic signatures of legumain. J Cell Physiol e31466.

4. Xu, B., Anderson, B.M., Mintern, J.D., Edgington‐Mitchell, L.E. (2024) TLR9‐dependent dendritic cell maturation promotes IL‐6‐mediated upregulation of cathepsin X. Immunol Cell Biol 102:787-800.

5. Xu, B., Anderson, B.M., Mountford, S.J., Thompson, P.E., Mintern, J.D., Edgington-Mitchell, L.E. (2024) Cathepsin X deficiency alters the processing and localisation of cathepsin L and impairs cleavage of a nuclear cathepsin L substrate. Biol Chem 405:351-365.

6. Ziegler, A.R., Dufour, A., Scott, N.E.*, Edgington-Mitchell, L.E.* (2024) Ion Mobility-Based Enrichment-Free N-Terminomics Analysis Reveals Novel Legumain Substrates in Murine Spleen. Mol Cell Prot 23:100714.

7. Bird, L.E., Edgington-Mitchell, L.E., Newton, H.J. (2023) Eat, prey, love: Pathogen-mediated subversion of lysosomal biology. Curr Opin Immunol 83:102344.

8. Lee, I.Y., Tantisirivat, P., Edgington-Mitchell, L.E. (2023) Chemical tools to image the activity of PAR-cleaving proteases. ACS Bio Med Chem Au 3:295-304.

9. Peach, C.J., Edgington-Mitchell, L.E., Schmidt, B.L., Bunnett, N.W. (2023) Protease-activated receptors in health and disease. Physiological Reviews 103:717-785.

10. Liu, H., Wilson, K.R., Firth, A.M., Macri, C., Schriek, P., Blum, A.B., Villar, J., Wormald, S., Shambrook, M., Xu, B., Lim, H.J., McWilliam, H., Hill, A.F., Edgington-Mitchell, L.E., Caminischi, I., Lahoud, M.H., Segura, E., Herold, M.J., Villadangos, J.A., Mintern, J.D. (2022) Ubiquitin-like protein 3 (UBL3) is required for MARCH ubiquitination of major histocompatibility complex class II and CD86. Nat Comm 13:1-15.

11. Kim, M.L., Hardy, M.Y. Edgington-Mitchell, L.E., Ramarathinam, S.H., Chung, S.Z., Russell, A.K., Currie, I., Sleebs, B.E., Purcell, A.W., Tye-Din, J.A., Wicks, I.P. (2021) Hydroxychloroquine inhibits the mitochondrial antioxidant system in activated T cells. iScience 24:103509.

12. Tu, H.T., Inoue, K., Chen, E., Anderson, B.M., Sawicki, C.M., Scheff, N.N., Tran, H.D., Kim, D.H., Alemu, R.G., Yang, L., Dolan, J.C., Liu, C.Z., Janal, M.N., Latorre, R., Jensen, D.D., Bunnett, N.W., Edgington-Mitchell, L.E.*, Schmidt, B.L.* (2021) Cathepsin S Evokes PAR2-Dependent Pain in Oral Squamous Cell Carcinoma Patients and Preclinical Mouse Models. Cancers 13:4697.

13. Tu, H.T., Jensen, D.D., Anderson, B.M., Chen, E., Jiminez, N.N., Scheff, N.N., Inoue, K., Tran, H.D., Dolan, J.C., Meek, T.A., Hollenberg, M.D., Liu, C.Z., Vanner, S.J., Janal, M.N., Bunnett, N.W., Edgington-Mitchell, L.E.*, Schmidt, B.L.* (2021) Legumain Induces Oral Cancer Pain by Biased Agonism of Protease-Activated Receptor-2. J Neurosci JN-RM-1211-20.

14. Mountford*, S.J., Anderson*, B.M., Xu, B., Tay, E.S. V., Szabo, M., Hoang, M., Diao, J., Aurelio, L., Campden, R. I., Lindström, E., Sloan, EK., Yates, R.M., Bunnett, N. W., Thompson, P.E., Edgington-Mitchell, L.E. (2020) Application of a Sulfoxonium Ylide Electrophile to Generate Cathepsin X-Selective Activity-Based Probes. ACS Chem Biol 15:718-727.

15. Anderson, B. M., de Almeida, L.G.N., Sekhon, H., Young, D., Dufour, A., Edgington-Mitchell, L.E. (2019) N-Terminomics/TAILS Profiling of Macrophages after Chemical Inhibition of Legumain. Biochem 59:329-340.