Lysosome positioning affects NLRP3 inflammasome activation

Matchett, B. J.; Green, J. P.; Seoane, P. I.; Owen, A.; Drobkiewicz, T.; Bennett, H.; Adamson, A.; Lopez-Castejon, G.; Hoyle, C.; Lowe, M.; Brough, D.

doi:10.1101/2025.03.21.644552

bioRxiv · 10.1101/2025.03.21.644552

Lysosome positioning affects NLRP3 inflammasome activation

Matchett, B. J.·Green, J. P.·Seoane, P. I.·Owen, A.·Drobkiewicz, T.·Bennett, H.·Adamson, A.·Lopez-Castejon, G.·Hoyle, C.·Lowe, M.·Brough, D.

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Abstract

The NLRP3 inflammasome, an important multi-molecular protein complex driving inflammation, is activated by multiple cellular stresses, including a loss of organelle homeostasis. Studies indicate that lysosome disruption can play a role in NLRP3 inflammasome activation, but whether lysosome positioning impacts NLRP3 inflammasome activation is currently unknown. Using HeLa and macrophage cell models, the effect of repositioning lysosomes to either the cell periphery or the perinuclear region on inflammasome activation was studied. Lysosome positioning to the cell periphery increased NLRP3 inflammasome activation in response to nigericin. This effect correlated with a change in the subcellular localisation of the inflammasome complex and an increase in its size. As macrophages at sites of tissue inflammation are exposed to environments known to influence lysosome position, these data help us understand how subcellular organelle reorganisation can regulate inflammation in response to inflammatory stimuli.

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Matchett, B. J., Green, J. P., Seoane, P. I., Owen, A., Drobkiewicz, T., Bennett, H., Adamson, A., Lopez-Castejon, G., Hoyle, C., Lowe, M., Brough, D.. 2025-03-25. Lysosome positioning affects NLRP3 inflammasome activation. https://doi.org/10.1101/2025.03.21.644552

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