# Disrupting the TRAF1/cIAP2 interaction attenuates inflammasome activation and protects against monosodium urate crystal–induced arthritis

## TL;DR

Disrupting the TRAF1/cIAP2 interaction reduces inflammation and protects against gout-like arthritis by limiting inflammasome activation.

## Contribution

The study identifies the TRAF1/cIAP2 interaction as a novel regulator of inflammasome activation and a potential therapeutic target for gout.

## Key findings

- Disrupting TRAF1/cIAP2 interaction reduces caspase-1 ubiquitination and IL-1β secretion in THP-1 cells.
- TRAF1V196A mice show reduced IL-1β levels and joint inflammation in a gout model.
- The TRAF1/cIAP2 axis is established as a key regulator of inflammasome-driven diseases.

## Abstract

Tumor necrosis factor receptor (TNFR)–associated factor 1 (TRAF1) regulates NF-κB signaling and is implicated in chronic autoimmune diseases characterized by persistent inflammation. In addition to its role in restraining linear ubiquitin assembly complex–mediated linear ubiquitination of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) to limit inflammasome activation, TRAF1 also stabilizes cellular inhibitor of apoptosis protein 2 (cIAP2) by protecting it from degradation. Notably, cIAP2 promotes inflammasome activation via K63-linked polyubiquitination of caspase-1. Here, we show that disrupting the TRAF1/cIAP2 interaction (V203A in humans; V196A in mice) reduces inflammasome activation. TRAF1V203A THP-1 cells exhibit diminished caspase-1 ubiquitination, leading to impaired IL-1β secretion. Similarly, TRAF1V196A mice produce significantly lower IL-1β levels after LPS challenge. In a monosodium urate crystal–induced arthritis model, TRAF1V196A mice show reduced joint inflammation, decreased synovial immune cell infiltration, and attenuated disease severity. These findings establish the TRAF1/cIAP2 axis as a key regulator of inflammasome activation and a potential therapeutic target for inflammasome-driven diseases such as gout.