# GADD45β inhibits RIPK3-mediated NF-κB activation by interfering with NEMO-RIPK1-RIPK3 interactions

## TL;DR

GADD45β limits RIPK3's activation of NF-κB, reducing inflammation during necroptosis without causing cell death.

## Contribution

GADD45β is identified as a novel, RHIM-independent regulator of RIPK3-mediated NF-κB signaling.

## Key findings

- GADD45β binds RIPK3 and disrupts NEMO-RIPK1-RIPK3 complex formation.
- GADD45β suppresses RIPK3-induced proinflammatory signaling and CXCL8 production.
- GADD45β enhances long-term cell survival under inflammatory stress.

## Abstract

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-κB signaling, promoting cytokine production and immunogenic responses. However, the regulatory mechanisms governing RIPK3-dependent NF-κB activation remain largely unclear. Here, we identify Growth Arrest and DNA Damage-inducible β (GADD45β) as a novel regulator of RIPK3 activities. We show that GADD45β directly binds RIPK3 in a RHIM-independent manner, interfering with NEMO-RIPK1-RIPK3 complex formation and limiting RIPK3-mediated NF-κB activation. Furthermore, inducible expression of GADD45β selectively suppresses RIPK3-induced proinflammatory signaling without promoting caspase-dependent apoptosis and markedly reduces CXCL8 (IL-8) production during necroptotic stimulation. GADD45β also improves long-term cellular survival under sustained inflammatory stress. Our findings reveal GADD45β as a critical modulator of RIPK3-driven immune responses and suggest a potential therapeutic strategy for fine-tuning immunogenic cell death.