TRIM36 catalyzes K63-linked ubiquitination of TAK1 to drive septic inflammation

The Toll-like receptor 4 (TLR4) pathway is critical for initiating innate immunity; however, its dysregulation drives pathological inflammation in diseases such as sepsis.

In the present study, we utilized septic patients, lipopolysaccharide (LPS)-induced mouse models, and LPS-treated mouse macrophages as well as human THP-1-derived macrophages to investigate the potential functions and molecular mechanisms of TRIM36 in sepsis.

Here, we identify tripartite motif protein 36 (TRIM36) as a key positive regulator that amplifies TLR4 signaling. TRIM36 expression was robustly upregulated in macrophages upon lipopolysaccharide (LPS) challenge. Mechanistically, TRIM36 directly bound to TGF-β-activated kinase 1 (TAK1) and catalyzed its K63-linked ubiquitination, a prerequisite for the activation of TAK1 and the downstream nuclear factor-κB (NF-κB) pathway. Functionally, genetic ablation of Trim36 in mice attenuated hypothermia, improved survival, and reduced cytokine production in an LPS-induced sepsis model. Consistently, in vitro knockdown of TRIM36 in human macrophages blunted LPS-induced signaling and the secretion of proinflammatory mediators. Furthermore, analysis of a public transcriptomic dataset revealed that elevated TRIM36 levels were associated with non-survival in patients with sepsis.

Collectively, our findings establish TRIM36 as a critical amplifier of TLR4-induced hyperinflammation and highlight its potential as a therapeutic target for sepsis.