Cell Death Discov 2025[Dec]; ? (?): ? PMID41354733show ga
Necroptosis is a highly inflammatory form of regulated cell death driven by Receptor-Interacting Protein Kinase 3 (RIPK3), which plays a crucial role in immune responses, inflammatory diseases, and tumor microenvironment modulation. Beyond driving cell death via MLKL phosphorylation, RIPK3 also activates NF-kappaB signaling, promoting cytokine production and immunogenic responses. However, the regulatory mechanisms governing RIPK3-dependent NF-kappaB activation remain largely unclear. Here, we identify Growth Arrest and DNA Damage-inducible beta (GADD45beta) as a novel regulator of RIPK3 activities. We show that GADD45beta directly binds RIPK3 in a RHIM-independent manner, interfering with NEMO-RIPK1-RIPK3 complex formation and limiting RIPK3-mediated NF-kappaB activation. Furthermore, inducible expression of GADD45beta selectively suppresses RIPK3-induced proinflammatory signaling without promoting caspase-dependent apoptosis and markedly reduces CXCL8 (IL-8) production during necroptotic stimulation. GADD45beta also improves long-term cellular survival under sustained inflammatory stress. Our findings reveal GADD45beta as a critical modulator of RIPK3-driven immune responses and suggest a potential therapeutic strategy for fine-tuning immunogenic cell death.
Cell+Death+Discov 2025 ; ? (?): ?
