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

Authors

Shijie Song, Dingnai Nie, Zulaya Abudureyimu, Yijin Kuang, Wen Li, Xiaodan Yang, Qiao Ling, Junli Sheng, Huiru He, Xiaolong You, Suwan Wu, Wenhao Lu, Yuling Fu, Shouhai Wu, Kang Chen, Shengfeng Hu

Published in

Inflammation research : official journal of the European Histamine Research Society ... [et al.]. Volume 75. Issue 1. Oct 17, 2026. Epub Oct 17, 2026.

Abstract

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.

PMID:
42892647
Bibliographic data and abstract were imported from PubMed on 18 Oct 2026.

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