Prof David Komander, Division Head | WEHI Researcher Profile

Q: Mechanisms of mitophagy

A highly studied form of mitophagy - a cellular process that leads to the destruction of damaged mitochondria by autophagy - is regulated by phosphorylated ubiquitin, and uncharacterised Lys6-linked ubiquitin chains. These specialised ubiquitin signals are generated by the ubiquitin kinase PINK1 and the ubiquitin E3 ligase Parkin. Importantly, mutations of PINK1 or Parkin lead to inherited forms of early-onset Parkinson’s disease. In the past five years, we have provided a detailed molecular description of the ubiquitin signals and enzymes involved in mitophagy. We are now keen to target the system with small molecules, which may be useful to treat neurodegenerative diseases.

Q: Mechanisms, functions and inhibitors of deubiquitinases

Deubiquitinases (or DUBs) are the enzymes that reverse ubiquitin signals, and hence affect all ubiquitin functions. Most importantly, the overproduction of a DUB can lead to the stabilisation of its substrates – a situation highly relevant, for example, with oncogenes, where it has been proposed that small molecule inhibitors of DUBs could initiate the removal of any protein, including so called ‘undruggables’. We study mechanisms and regulation of DUBs at the structural, biochemical and physiological level. Uncovering the function and substrates of DUBs will be essential to provide new drug targets, and understanding their structure, mechanism and regulation enables drug discovery.

Q: New tools to enable ubiquitin studies

Any science is only as good as the tools available to study it. Our research of unstudied atypical ubiquitin signals and of ubiquitin chain architecture, require the development of new biochemical methods and reagents, which then also give the opportunity to study ubiquitination in unprecedented detail and unveil new biology. In particular, we have developed methods to study ubiquitin chains using linkage specific deubiquitinases (UbiCREST), and affimers that act similarly to antibodies in detecting understudied ubiquitin chain types. We work in close collaboration with Dr Andrew Webb to develop new tools to study ubiquitin signals by mass-spectrometry (Ub-clipping).

About

We focus on the modifier ubiquitin, a small protein that modifies other proteins in a variety of distinct ways, known as the ‘ubiquitin code’.

Ubiquitination most commonly leads to destruction of the modified protein, but can also change its activation, interactions or localisation. Much of our work aims to enable studies of ubiquitin signals.

A biological focus of the lab are deubiquitinases (DUBs) that remove ubiquitin from proteins. Using structural biology and biophysics, we have unraveled many mechanistic and regulatory principles of how DUBs cleave ubiquitin modifications.

Using preclinical models and in collaboration with human geneticists, we ascribe cellular and physiological function to select enzymes. Finally, in collaboration with industry, we are developing the first enzyme-specific DUB inhibitors, which may become new treatments for cancer and neurodegeneration.

Education

Joint appointments

Publications

Selected publications from Prof David Komander

2026;

Schenk P, Devine SM, Cobbold SA, Geoghegan ND, Kyran EL, Ang C-S, Alexandrovics JA, Calleja DJ, Multari DH, Vaibhav V, Lu BGC, Klemm TA, Dagley LF, Lowes KN, Williamson NA, Eichhorn PJA, Ng AP, Feltham R, Komander D. Global analysis of cancer cell responses to USP9X inhibition. The EMBO Journal. 2026;:10.1038/s44318-026-00742-y

Chua NK, González-Robles TJ, Reddington CJ, Dudley-Fraser J, Birkinshaw RW, Han J, Solano A, Wong SW, Kochańczyk T, Peter JJ, Nakasone MA, Aust F, Munro J, Tong YH, Iskander J, Abeysekera W, Garnham A, Huckstep H, Ritchie ME, Wertz I, Hymowitz S, Kumar S, Conaway RC, Privé GG, Bullock AN, Babon JJ, Klevit RE, Lorenz S, Ciulli A, Fischer ES, Thomä NH, Nowak RP, Schulman BA, Rapé M, Rittinger K, Pagan JK, Bahlo M, Mackay JP, Mace PD, Lima CD, Hay RT, Komander D, Lechtenberg BC, Joazeiro CAP, Pagano M, Hofmann K, Feltham R. The E3-ome gene-centric compendium reveals the human E3 ligase landscape. Cell. 2026;189(7):10.1016/j.cell.2026.01.029

Liu H, Francis L, Dagley LF, Cobbold SA, Webb AI, Komander D, Villadangos JA, Mintern JD. Major histocompatibility class II in murine antigen presenting cells is modified with a branched K63 and K11-linked ubiquitin chain. Scientific Reports. 2025;15(1):10.1038/s41598-025-25817-4

Kumari N, Wright SC, Witham CM, Monserrat L, Palafox M, Richard JLC, Costa C, Elkabets M, Agostino M, Klemm T, Eccles MK, Garnham A, Wu T, Nilsson JA, Walz N, Venugopal V, Cerra A, Vasilevski N, Bridgeman SC, Bassi S, Saei A, Helal M, Neundorf P, Riedel A, Rosenfeldt M, Gill J, Pahor N, Hartmann O, Chung J, Sidhu SS, Moderau N, Jha S, Rodon J, Diefenbacher ME, Komander D, Serra V, Eichhorn P. USP10/GSK3B-mediated inhibition of PTEN drives resistance to PI3K inhibitors in breast cancer. Journal of Clinical Investigation. 2025;135(22):10.1172/jci180927

Wu X, Devine SM, Go M, Nguyen JV, Lu BGC, Loi K, Kuchel NW, Lowes KN, Mitchell JP, Lessene G, Komander D, Call ME, Call MJ. Divergent resistance pathways amongst SARS-CoV-2 PLpro inhibitors highlight the need for scaffold diversity. PLOS Pathogens. 2025;21(9):10.1371/journal.ppat.1013468

Marapana D, Cobbold SA, Pasternak M, Shami GJ, Ralph SA, Lopaticki S, Yousef J, Vaibhav V, Dagley LF, Komander D, Cowman AF. Functional characterisation of components in two Plasmodium falciparum Cullin-RING-Ligase complexes. Scientific Reports. 2025;15(1):10.1038/s41598-025-05342-0

Wang XS, Jiou J, Cerra A, Cobbold SA, Jochem M, Mak KHT, Corcilius L, Silke J, Payne RJ, Goddard-Borger ED, Komander D, Lechtenberg BC. The RBR E3 ubiquitin ligase HOIL-1 can ubiquitinate diverse non-protein substrates in vitro. Life Science Alliance. 2025;8(6):10.26508/lsa.202503243

Callegari S, Kirk NS, Gan ZY, Dite T, Cobbold SA, Leis A, Dagley LF, Glukhova A, Komander D. Structure of human PINK1 at a mitochondrial TOM-VDAC array. Science. 2025;388(6744):10.1126/science.adu6445

M. Bader S, Calleja DJ, Devine SM, Kuchel NW, Lu BGC, Wu X, Birkinshaw RW, Bhandari R, Loi K, Volpe R, Khakham Y, Au AE, Blackmore TR, Mackiewicz L, Dayton M, Schaefer J, Scherer L, Stock AT, Cooney JP, Schoffer K, Maluenda A, Kleeman EA, Davidson KC, Allison CC, Ebert G, Chen G, Katneni K, Klemm TA, Nachbur U, Georgy SR, Czabotar PE, Hannan AJ, Putoczki TL, Tanzer M, Pellegrini M, Lechtenberg BC, Charman SA, Call MJ, Mitchell JP, Lowes KN, Lessene G, Doerflinger M, Komander D. A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID. Nature Communications. 2025;16(1):10.1038/s41467-025-57905-4