TRIM26 positively regulates the inflammatory immune response through K11-linked ubiquitination of TAB1

Protein ubiquitination plays an important role in the regulation of TGF-beta-activated kinase 1 (TAK1)-mediated NF-kappa B activation. It is well established that TAK1 activation is tightly regulated with its binding partners, TAK1-binding proteins (TAB1-3). However, the tight regulation of TAK1 activation remains elusive. Here, using Trim26-knockout mice and Trim26-transgenic mice, we found that TRIM26 acts as a positive regulator of TAK1 activation by ubiquitinating its binding partner TAB1. Knockout of Trim26 inhibited TAK1 activation and downstream kinases activation, thus decreasing the induction of proinflammatory cytokines following LPS, TNF-alpha, and IL-1 beta stimulation. Mechanistically, TRIM26 catalyzes the K11-linked polyubiquitination of TAB1 at Lys294, Lys319, and Lys335 to enhance the activation of TAK1 and subsequent NF-kappa B and MAPK signaling. Consequently, Trim26 deficiency protects mice from LPS-induced septic shock in vivo. Moreover, Trim26 deficiency attenuates the severity of dextran sodium sulfate (DSS)-induced colitis. Thus, these finding provides a novel insight into how TAK1 activation is regulated through TRIM26-mediated ubiquitination of TAB1 and reveals the new function of TRIM26 in the regulation of the inflammatory innate immune response.

Automated summary

The study reveals that TRIM26 positively regulates TAK1 activation by ubiquitinating its binding partner TAB1. Trim26 deficiency reduces the induction of inflammatory cytokines, protecting mice from septic shock and attenuating the severity of colitis.