RIPK3mediated

RIPK3-mediated refers to signaling driven by receptor-interacting serine/threonine-protein kinase 3 (RIPK3) that leads to necroptosis, a form of programmed necrotic cell death. In this pathway, RIPK3 is recruited to a death-indomain containing complex often called the necrosome, where it becomes activated and phosphorylates the downstream substrate mixed lineage kinase domain-like protein (MLKL). Phosphorylated MLKL oligomerizes and translocates to the plasma membrane, where it disrupts membrane integrity and triggers cell lysis. The release of cellular contents and danger signals promotes inflammation and can influence immune responses.

Activation of RIPK3 typically requires signals such as tumor necrosis factor (TNF) family cytokines in contexts where caspase-8 activity is inhibited or absent, as well as other stimuli including certain pattern recognition receptor ligands (for example, TLR3/4) and viral infections. Although RIPK3 commonly acts in a RIPK1-dependent manner, ZBP1 and other sensors can engage RIPK3 through RHIM-domain interactions in some contexts, sometimes with reduced reliance on RIPK1. Regulation is tight: caspase-8 and cIAPs act as brakes to necroptosis, while pharmacological inhibitors of RIPK1 or RIPK3 and MLKL can block the pathway.

Biological and clinical relevance includes roles in host defense against pathogens, as well as contributions to tissue injury and inflammatory diseases when necroptosis is uncontrolled. In addition to its kinase-dependent necroptotic function, RIPK3 can participate in kinase-independent signaling that modulates inflammation. Because of its involvement in disease and immune responses, the RIPK3 pathway is a target of interest for therapeutic intervention to modulate necroptosis.