Necroptosis is a regulated, lytic form of cell death with important roles in inflammation and immunity. Unlike apoptosis, necroptosis is pro-inflammatory and characterized by the rupture of the cell membrane. This mode of cell death is orchestrated primarily through the actions of a pseudokinase known as mixed lineage kinase-like protein (MLKL).
Upon stimulation by inflammatory signals—such as tumor necrosis factor alpha (TNF-α)—the necroptotic pathway is initiated. Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) phosphorylates MLKL, triggering a conformational change that promotes MLKL oligomerization. This activated MLKL then translocates from the cytosol to the plasma membrane. Once at the membrane, MLKL integrates into lipid bilayers, causing membrane permeabilization and ultimately, cell lysis.
The cascade involving RIPK3 and MLKL underscores a critical regulatory mechanism of necroptosis. Because necroptosis results in the release of cellular contents, including damage-associated molecular patterns (DAMPs), it contributes to the amplification of immune responses. This makes it highly relevant to conditions such as autoimmune diseases, neurodegeneration, and certain infections.
Ongoing research into the molecular players and downstream effects of necroptosis aims to identify potential therapeutic targets. Inhibiting MLKL translocation or disrupting its interaction with the plasma membrane could be promising strategies for modulating inflammation in pathological contexts.
Overall, the study of necroptosis and the MLKL-RIPK3 axis reveals essential insights into the body’s response to cellular stress and damage, with broad implications across immunology and disease pathology.
Source: https:// – Courtesy of the original publisher.
