Mr Zikou Liu - Cell Signalling and Cell Death division

Mr Zikou Liu - Cell Signalling and Cell Death division

Davis Auditorium
Start Time: 
Mon, 11/03/2019 - 3:00pm
End Time: 
Mon, 11/03/2019 - 4:00pm

Oligomerisation-driven MLKL ubiquitylation during necroptosis

​PhD Completion seminar

Programmed cell death (PCD) is a regulated cell suicide process that removes undesirable or damaged cells from a multicellular organism to achieve proper development, to maintain homeostasis and to protect against pathogen attack. Mixed-lineage kinase domain-like (MLKL) is the executioner in the caspase8-independent form of PCD called necroptosis. Upon necroptotic stimulation, MLKL is phosphorylated, oligomerizes and translocates to biological membranes. MLKL ubiquitylation has also been observed in the context of necroptotic signalling, yet the detailed mechanism and function of MLKL ubiquitylation remain unknown.

Zikou Liu, during his PhD, focused on investigating how MLKL-ubiquitylation is regulated and what role it plays in necroptosis signalling. With the technique of ubiquitylated protein enrichment and membrane fractionation, he has found that MLKL-ubiquitylation happens at biological membranes, is triggered specifically by necroptotic stimuli and coincides with MLKL oligomerisation. He has also found that MLKL protein levels are down-regulated after activation and that this is blocked by proteasome and lysosome inhibitors, indicating a potential role for MLKL-ubiquitylation in regulating necroptosis signaling. Necrosulfamide (NSA) can block human MLKL-induced cell death without interfering with its phosphorylation, oligomerization and membrane translocation, Interestingly, NSA blocks ubiquitylation of human MLKL, placing ubiquitylation after oligomerisation and providing a new tool for the investigation of novel components that may regulate necroptosis.