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

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.

Author information

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.

Correspondence to Liyun Shi.

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The authors declare no competing interests.

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Keywords

  • TLR4
  • Lamtor5
  • mTORC1
  • TFEB
  • Autolysosome