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CUL4B negatively regulates Toll-like receptor-triggered proinflammatory responses by repressing Pten transcription

Cellular & Molecular Immunology volume 18, pages 339–349 (2021)Cite this article

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Abstract

Toll-like receptors (TLRs) play critical roles in innate immunity and inflammation. The molecular mechanisms by which TLR signaling is fine-tuned remain to be completely elucidated. Cullin 4B (CUL4B), which assembles the CUL4B-RING E3 ligase complex (CRL4B), has been shown to regulate diverse developmental and physiological processes by catalyzing monoubiquitination for histone modification or polyubiquitination for proteasomal degradation. Here, we identified the role of CUL4B as an intrinsic negative regulator of the TLR-triggered inflammatory response. Deletion of CUL4B in macrophages increased the production of proinflammatory cytokines and decreased anti-inflammatory cytokine IL-10 production in response to pathogens that activate TLR3, TLR4, or TLR2. Myeloid cell-specific Cul4b knockout mice were more susceptible to septic shock when challenged with lipopolysaccharide, polyinosinic-polycytidylic acid or Salmonella typhimurium infection. We further demonstrated that enhanced TLR-induced inflammatory responses in the absence of CUL4B were mediated by increased GSK3β activity. Suppression of GSK3β activity efficiently blocked the TLR-triggered increase in proinflammatory cytokine production and attenuated TLR-triggered death in Cul4b mutant mice. Mechanistically, CUL4B was found to negatively regulate TLR-triggered signaling by epigenetically repressing the transcription of Pten, thus maintaining the anti-inflammatory PI3K-AKT-GSK3β pathway. The upregulation of PTEN caused by CUL4B deletion led to uncontrolled GSK3β activity and excessive inflammatory immune responses. Thus, our findings indicate that CUL4B functions to restrict TLR-triggered inflammatory responses through regulating the AKT-GSK3β pathway.

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Acknowledgements

We thank Prof. Chengjiang Gao and Prof. Wei Zhao for their critically reading of the paper. This work was supported by the National Natural Science Foundation of China (81571523 and 31872810), the Natural Science Foundation of Shandong Province (ZR2016HZ01), and the Key Research and Development Program of Shandong Province (2016ZDJS07A08 and 2017GSF218027).

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Authors and Affiliations

  1. Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China

    Yu Song, Peishan Li, Liping Qin, Zhiliang Xu, Baichun Jiang & Yaoqin Gong

  2. Key Laboratory of Experimental Teratology, Ministry of Education, Department of Immunology, School of Basic Medical Science, Shandong University, Jinan, Shandong, China

    Chunhong Ma

  3. State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China

    Changshun Shao

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Song, Y., Li, P., Qin, L. et al. CUL4B negatively regulates Toll-like receptor-triggered proinflammatory responses by repressing Pten transcription. Cell Mol Immunol 18, 339–349 (2021). https://doi.org/10.1038/s41423-019-0323-0

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