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

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

Agrata R, Komander D. Ubiquitin—A structural perspective. Molecular Cell. 2025;85(2):10.1016/j.molcel.2024.12.015

Gan ZY, Komander D, Callegari S. Reassessing kinetin’s effect on PINK1 and mitophagy. Autophagy. 2024;20(11):10.1080/15548627.2024.2395144

Michel MA, Scutts S, Komander D. Secondary interactions in ubiquitin-binding domains achieve linkage or substrate specificity. Cell Reports. 2024;43(8):10.1016/j.celrep.2024.114545

Nguyen-Dien GT, Townsend B, Kulkarni PG, Kozul K-L, Ooi SS, Eldershaw DN, Weeratunga S, Liu M, Jones MJ, Millard SS, Ng DC, Pagano M, Bonfim-Melo A, Schneider T, Komander D, Lazarou M, Collins BM, Pagan JK. PPTC7 antagonizes mitophagy by promoting BNIP3 and NIX degradation via SCFFBXL4. EMBO Reports. 2024;25(8):10.1038/s44319-024-00181-y

Wu X, Go M, Nguyen JV, Kuchel NW, Lu BGC, Zeglinski K, Lowes KN, Calleja DJ, Mitchell JP, Lessene G, Komander D, Call ME, Call MJ. Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape. Nature Communications. 2024;15(1):10.1038/s41467-024-50566-9

Davidson S, Shibata Y, Collard S, Zheng H, Kong K, Sun JM, Laohamonthonkul P, Cerra A, Kratina T, CIRCA, AADRY, Li MWY, Russell C, van Beek A, Kirk EP, Walsh R, Alqanatish J, Almojali A, Alsuwairi W, Alrasheed A, Lalaoui N, Gray PE, Komander D, Masters SL. Dominant negative OTULIN-related autoinflammatory syndrome. Journal of Experimental Medicine. 2024;221(6):10.1084/jem.20222171

Lechtenberg BC, Komander D. Just how big is the ubiquitin system?. Nature Structural & Molecular Biology. 2024;31(2):10.1038/s41594-023-01208-z