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

Abstract

Protein ubiquitination plays an important role in the regulation of TGF-β-activated kinase 1 (TAK1)-mediated NF-κB 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-α, and IL-1β stimulation. Mechanistically, TRIM26 catalyzes the K11-linked polyubiquitination of TAB1 at Lys294, Lys319, and Lys335 to enhance the activation of TAK1 and subsequent NF-κB 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.

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Fig. 1: TRIM26 positively regulates TLRs-induced production of proinflammatory cytokines.
Fig. 2: TRIM26 enhances TLRs-induced NF-κB and MAPK signaling.
Fig. 3: TRIM26 mediates polyubiquitination of TAB1 and interacts with TAB1.
Fig. 4: TRIM26 targets Lys294, 319, and 335 of TAB1 for K11-linked polyubiquitination.
Fig. 5: TRIM26 enhances phosphorylation and complex assembly of TAK1.
Fig. 6: TRIM26 deficiency protects mice from LPS-induced septic shock.
Fig. 7: TRIM26 deficiency attenuates dextran sodium sulfate (DSS)-induced colitis.

Data availability

The data within the article and its Supplementary Information files that support this study are available from the authors upon request.

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Acknowledgements

We thank Dr. Hui Xiao (Institut Pasteur of Shanghai, CAS, Shanghai, China) for the Flag-TAB2 expression plasmid; Dr. Chen Wang (School of Life Science and Technology, China Pharmaceutical University, China) for the HA-K11R expression plasmid; and Dr. Michael Karin (University of California at San Diego, San Diego, CA) for the expression plasmids of TRAF6, IKKβ, and TAK1; Dr. Zhengfan Jiang (Peking University) for the Flag-ITCH expression plasmid; Dr. Ran Huo (Nanjing Medical University) for the Flag-RNF114 expression plasmid; Dr. Chao Xu (Shandong Provincial Hospital Affiliated to Shandong University) for the Flag-MEKK1 expression plasmid.

Funding

This work was supported by the Natural Science Foundation of China (81930039, 31730026, 81525012 to CG and 31900680 to BL). This work was also supported by the Postdoctoral Science Foundation of China (BX201700146 to BL) and Shandong Provincial Natural Science Foundation (ZR2018BC021 to BL).

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CG conceived and designed the study. JZ and BC performed most of the experiments with help from ZS. LZ, YZ, CM, and FY contributed to the discussion and provided reagents. CG and BL supervised the study. JZ and BL analyzed the data. CG, BL, and JZ wrote the paper.

Corresponding authors

Correspondence to Bingyu Liu or Chengjiang Gao.

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The authors declare no competing interests.

Ethical approval

All mouse experiments were carried out according to the Guidelines of the China Animal Welfare Legislation, as approved by the Ethics Committee of Scientific Research of Shandong University Qilu Hospital, Jinan, Shandong Province, China (Permit number: KYLL-2017(KS)-361).

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Zhao, J., Cai, B., Shao, Z. et al. TRIM26 positively regulates the inflammatory immune response through K11-linked ubiquitination of TAB1. Cell Death Differ (2021). https://doi.org/10.1038/s41418-021-00803-1

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