Dr Andre Samson, Inflammation division

Dr Andre Samson, Inflammation division

Location: 
Online
Start Time: 
Wed, 21/10/2020 - 1:00pm
End Time: 
Wed, 21/10/2020 - 2:00pm

Wednesday seminar hosted by Associate Professor James Murphy

Dr Andre Samson
Senior Research Officer, Murphy Laboratory, Inflammation division - Infection, Inflammation and Immunity Theme
 

MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosi

Necroptosis is a caspase-independent form of programmed cell death that contributes to many health disorders including inflammatory bowel disease and ischemic kidney injury. Indicative of this broad role in disease, GSK, AstraZeneca, Denali-Sanofi and the Chinese Ministry of Science and Technology are now competing to develop the first anti-necroptotic drug. Prototypical necroptotic signaling involves transduction along the RIPK1-RIPK3-MLKL axis. Receptor Interacting Protein Kinase-3 (RIPK3) was identified as an essential downstream mediator of necroptosis in 2009, while Mixed lineage kinase domain-like protein (MLKL) was discovered as the terminal effector of necroptosis in 2012. Owing to the recency of these discoveries, our understanding of the terminal steps in necroptosis remains incomplete.

To address this gap in knowledge, we have been compiling an array of affinity reagents to visualise the in situ activation and intracellular movements of endogenous RIPK1, RIPK3 and MLKL during necroptosis. In this seminar, Andre will introduce a comprehensive toolkit for the immunofluorescent detection of the necroptotic pathway. This single cell imaging approach has allowed precise quantitation of human MLKL as it transitions from its basal state in the cytosol into micron-sized oligomers at the plasma membrane that then ultimately trigger necroptotic death. These data have also uncovered two rate-limiting checkpoints that control necroptosis: 1) a trafficking mechanism that regulates the movement of MLKL to the cell periphery, and 2) a threshold mechanism that dictates the amount of MLKL required at the plasma membrane to trigger necroptosis. Strikingly, this threshold mechanism operates at intercellular junctions and renders necroptosis “contagious” by accelerating the death of adjoining neighbouring cells. Collectively, these studies have identified novel avenues for anti-necroptotic intervention and pave the way for even higher resolution analyses of life-and-death signaling by RIPK1, RIPK3 and MLKL.

 

Join via TEAMS
Including Q&A session​