Partners in Crime: The Interplay of Proteins and Membranes in Regulated Necrosis

Abstract

Pyroptosis, necroptosis, and ferroptosis are well-characterized forms of regulated necrosis that have been associated with human diseases. During regulated necrosis, plasma membrane damage facilitates the movement of ions and molecules across the bilayer, which finally leads to cell lysis and release of intracellular content. Therefore, these types of cell death have an inflammatory phenotype. Each type of regulated necrosis is mediated by a defined machinery comprising protein and lipid molecules. Here, we discuss how the interaction and reshaping of these cellular components are essential and distinctive processes during pyroptosis, necroptosis, and ferroptosis. We point out that although the plasma membrane is the common target in regulated necrosis, different mechanisms of permeabilization have emerged depending on the cell death form. Pore formation by gasdermins (GSDMs) is a hallmark of pyroptosis, while mixed lineage kinase domain-like (MLKL) protein facilitates membrane permeabilization in necroptosis, and phospholipid peroxidation leads to membrane damage in ferroptosis. This diverse repertoire of mechanisms leading to membrane permeabilization contributes to define the specific inflammatory and immunological outcome of each type of regulated necrosis. Current efforts are focused on new therapies that target critical protein and lipid molecules on these pathways to fight human pathologies associated with inflammation.

Severe COVID-19: NLRP3 Inflammasome Dysregulated

“…This necessary additional endogenous adjuvant activity is provided by pyroptotic cell death regulated by Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation. These multiprotein complexes form in the cytosol and drive caspase-1 cleavage and the secretion of the pro-inflammatory cytokines IL-1β and IL-18 and other damage-associated molecular patterns (DAMPs) ( 6 ). This stimulation of antigen presentation to benefit the induction of an adaptive immune response comes with a cost, because these danger signals give rise to toxicity and are the cause of a rise in body temperature and therefore need to be tightly controlled ( 7 ).…”

Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics

“…Increase in cytosolic Ca 2+ , cell swelling, rounding, as well as plasma membrane breakdown have been described as hallmarks for necroptosis and pyroptosis [13,24,25]. In contrast to apoptosis, such increase in cytosolic Ca 2+ is commonly associated with plasma membrane damage during these forms of regulated necrosis [26]. To assess whether these cellular alterations also take place during ferroptosis, we measured cytosolic Ca 2+ levels in parallel to changes in cell morphology and plasma membrane breakdown by live-cell confocal imaging (Fig.…”

Pore formation in regulated cell death

“…Chief among them, the inflammatory cytokines IL‐1β and IL‐18 can be released via these pores through non‐conventional mechanisms in a cell death‐independent manner (Heilig et al , 2018). The passive transport of molecules through GSDMs pores also leads to osmotic imbalance, cell bursting, and final death, which allows the unspecific release of larger damage‐associated molecular patterns (DAMPS) from cells (Broz et al , 2020; Ros et al , 2020). One interesting aspect that remains a matter of debate is whether GSDMs pores could impact the events that anticipate cell death by regulating the size of the molecules that are released from pyroptotic cells.…”