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The metabolic regulator Lamtor5 suppresses inflammatory signaling via regulating mTOR-mediated TLR4 degradation

Cellular & Molecular Immunology volume 17, pages 1063–1076 (2020)Cite this article

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Abstract

Comprehensive immune responses are essential for eliminating pathogens but must be tightly controlled to avoid sustained immune activation and potential tissue damage. The engagement of TLR4, a canonical pattern recognition receptor, has been proposed to trigger inflammatory responses with different magnitudes and durations depending on TLR4 cellular compartmentalization. In the present study, we identify an unexpected role of Lamtor5, a newly identified component of the amino acid-sensing machinery, in modulating TLR4 signaling and controlling inflammation. Specifically, Lamtor5 associated with TLR4 via their LZ/TIR domains and facilitated their colocalization at autolysosomes, preventing lysosomal tethering and the activation of mTORC1 upon LPS stimulation and thereby derepressing TFEB to promote autophagic degradation of TLR4. The loss of Lamtor5 was unable to trigger the TFEB-driven autolysosomal pathway and delay degradation of TLR4, leading to sustained inflammation and hence increased mortality among Lamtor5 haploinsufficient mice during endotoxic shock. Intriguingly, nutrient deprivation, particularly leucine deprivation, blunted inflammatory signaling and conferred protection to endotoxic mice. This effect, however, was largely abrogated upon Lamtor5 deletion. We thus propose a homeostatic function of Lamtor5 that couples pathogenic insults and nutrient availability to optimize the inflammatory response; this function may have implications for TLR4-associated inflammatory and metabolic disorders.

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Acknowledgements

This work was supported by National Natural Scientific Funds (81770014 and 81470210), the National Key Research and Development Program Project (2018YFC1705900), the Natural Science Foundation of Jiangsu Province Fund (BK20180824), financial support for the Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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  1. These authors contributed equally: Wei Zhang, Ningtong Zhuang

Authors and Affiliations

  1. Department of Immunology and Medical Microbiology, Nanjing University of Chinese Medicine, 210046, Nanjing, China

    Wei Zhang, Xiaoyi Liu, Long He & Liyun Shi

  2. Key Lab of Inflammation and Immunoregulation, Hangzhou Normal University School of Medicine, Hangzhou, 310036, Zhejiang, China

    Ningtong Zhuang, Yan He, Hang Zhang, Yanhua Kang, Dakang Xu & Liyun Shi

  3. University of Maryland, College Park, MD, 20742, USA

    Paween Mahinthichaichan

  4. Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, 210046, Nanjing, China

    Yin Lu

  5. The College of Pharmacology, Nanjing University of Chinese Medicine, 210023, Nanjing, China

    Qinan Wu

  6. Faculty of Medical Laboratory Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 227 Chongqing Road South, 200025, Shanghai, China

    Dakang Xu

  7. Hudson Institute of Medical Research, Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3800, Australia

    Dakang Xu

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Contributions

L.S. designed the project. W.Z., N.Z., L.H., X.L., Y.H., M.P., H.Z. and Y.K. performed experiments and analyzed data. Y.L., D.X. and Q.W. contributed to the experimental material and provided insightful suggestions. L.S. and W.Z. wrote the manuscript.

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Correspondence to Liyun Shi.

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Zhang, W., Zhuang, N., Liu, X. et al. The metabolic regulator Lamtor5 suppresses inflammatory signaling via regulating mTOR-mediated TLR4 degradation. Cell Mol Immunol 17, 1063–1076 (2020). https://doi.org/10.1038/s41423-019-0281-6

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