Necrotic cell death has long been regarded as an uncontrolled consequence of chemical or mechanical insult. Recent work has revealed it to be intricately programmed and deliberate in certain scenarios like infection.
This programmed necrosis or ‘necroptosis’ is triggered by a cascade of intracellular signals. The last known member in this signal relay is the protein MLKL, yet its role in affecting cell death remains a strong topic of contention. We aim to fill a fundamental knowledge gap in the field of necroptosis; What are the regulatory factors that limit and activate the killing activity of MLKL? We hypothesize that MLKL’s killing activity relies on phosphorylation, as we recently published, but also on ubiquitination, lipid modification and protein complex formation. We further propose that cells are equipped with mechanisms to restrain and modulate the killer activity of activated MLKL. Our established set of biological tools ranges from exclusive mouse strains that will allow us to characterize how MLKL activity is repressed in vivo, to a library of rationally designed MLKL mutant cell lines that will permit us to precisely map the landscape of post-translational modifications that modulate its movements at the molecular and cellular level.Dysregulated necroptotic cell death is a suspect in the etiology and pathology of debilitating autoimmune disease. Likewise, necroptotic cell death has been implicated in the ischemia-reperfusion injury that can occur following stroke, cardiac infarction and organ transplantation. Identifying and characterizing the regulatory checkpoints in MLKL function will open up a swathe of options for the therapeutic inhibition of necroptosis, feeding directly into our already established anti-necroptosis drug screening and development program.
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FEATURED Journal article
Identification of MLKL membrane translocation as a checkpoint in necroptotic cell death using Monobodies
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Scholarly Works
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Honours, Awards and Fellowships
NHMRCF - NHMRC Fellowship
CJMARTIN - C.J. Martin Research Fellowship (National Health & Medical Research Council, Australia)
Credentials
Positions
Honorary
Medical Biology (W.E.H.I.)
Education
PhD-Medicine, Dentistry & Health Sciences
University of Melbourne
Science
University of Melbourne
Biomedical Science
University of Melbourne