Shedding light on the regulation and execution of necroptosis

Uris Lianne Ros Quincoces

Uris Lianne Ros Quincoces1, Ana J Garcia Saez1

1CECAD, Joseph-Stelzmann-Stra├če, 26, Germany

Necroptosis is an inflammatory form of regulated cell death implicated in neurodegeneration, cancer and immunity against infection. Execution of necroptosis depends on Mixed Lineage Kinase domain-Like (MLKL), a pseudokinase whose activity remains poorly understood. We combine membrane biophysics with biochemistry, and structural and cell biology to understand MLKL function and regulation. We identified that pore formation is a core mechanism in necroptosis, which is linked to the activation of calcium fluxes through the plasma membrane and the endoplasmic reticulum. To get insight into the structure-function relation of MLKL, we investigate the activity and biological function of different MLKL isoforms. We uncovered a fundamental mechanism of how MLKL molecules work to trigger necroptosis. Specifically, we found a new site in MLKL that is so central to its function that interfering with it completely abrogates the necroptosis activity of naturally occurring isoforms. MLKL isoforms counterbalance each other to modulate necroptosis sensitivity, which may play a role in fine-tuning the level of inflammation in response to gram-negative bacterial infection. We exploited this structure-function relation knowledge and devised a new strategy for specifically targeting MLKL with a new class of allosteric inhibitors. These inhibitors emerged as a new tool to study the consequences of MLKL chemical inhibition in mouse models, opening new possibilities for the treatment of necroptosis-related diseases in humans.

 

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