Protein-lipid Interactions in Mechanisms of Cell Death

schematic.

Cartoon representation of MLKL and potential interactions that results in membrane permeabilization. Figures adapted from Murphy, Immunity 39(3):443-453 & Czabotar, FEBS J. 282(22):4268-4278

Overview

One of the major challenges of cancer therapies is drug-resistance development. Cancer cells are able to develop resistance to apoptosis, a form of programmed cell death, and novel therapies are searching to target alternative routes for regulated cell death, such as necroptosis.

In this modality, a cascade of signaling events result in permeabilization of the plasma membrane. Leakage of internal cellular components can trigger an inflammatory response that generates a microenvironment suitable for oncogenesis and tumor metastasis around the cell. There is urgent need to understand the mechanism and regulation of this dual effect of necroptosis in cancer, i.e. death of the cell vs. local oncogenic environment, and leverage the mechanism for anti-cancer therapies. Necroptosis is controlled by activation of receptor-interacting protein (RIP) kinases followed by phosphorylation and translocation of MLKL to the plasma membrane. We are particularly interested on the role of specific membrane lipids in regulation of the membrane targeting and rupturing mechanism of MLKL. We are currently examining protein mutations and how they impact the interaction of the protein with complex model bilayers. This is an exciting project we have with the Atilla Lab in Chemistry at UB (https://atillalab.org/)