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Sci Immunol. 2017 Oct 27;2(16). pii: eaak9573. doi: 10.1126/sciimmunol.aak9573.

Lysosome signaling controls the migration of dendritic cells.

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INSERM U932 Immunité et Cancer, Institut Curie, Paris Sciences & Lettres Research University, F-75248 Paris, Cedex 05, France.
INSERM U932 Immunité et Cancer, Institut Curie, Paris Sciences & Lettres Research University, F-75248 Paris, Cedex 05, France.
Institut Curie, Paris Sciences & Lettres Research University, CNRS, UMR 144, F-75005 Paris, France.
Institut Pierre-Gilles de Gennes, Paris Sciences & Lettres Research University, F-75005 Paris, France.
Telethon Institute of Genetics and Medicine (TIGEM), I-80078 Pozzuoli, Naples, Italy.
Université Paris-Sud, Université Paris-Saclay, F-91405 Orsay, France.
Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Institute FIRC (Italian Foundation for Cancer Research) of Molecular Oncology (IFOM-FIRC), I-20139 Milano, Italy.
Istituto di Genetica Molecolare-Consiglio Nazionale delle Ricerche (IGM-CNR), Via Abbiategrasso 207, I-27100 Pavia, Italy.
Medical Genetics, Department of Translational Medicine, Federico II University, I-80131 Naples, Italy.
Department of Molecular and Human Genetics, Baylor College of Medicine and Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.


Dendritic cells (DCs) patrol their environment by linking antigen acquisition by macropinocytosis to cell locomotion. DC activation upon bacterial sensing inhibits macropinocytosis and increases DC migration, thus promoting the arrival of DCs to lymph nodes for antigen presentation to T cells. The signaling events that trigger such changes are not fully understood. We show that lysosome signaling plays a critical role in this process. Upon bacterial sensing, lysosomal calcium is released by the ionic channel TRPML1 (transient receptor potential cation channel, mucolipin subfamily, member 1), which activates the actin-based motor protein myosin II at the cell rear, promoting fast and directional migration. Lysosomal calcium further induces the activation of the transcription factor EB (TFEB), which translocates to the nucleus to maintain TRPML1 expression. We found that the TRPML1-TFEB axis results from the down-regulation of macropinocytosis after bacterial sensing by DCs. Lysosomal signaling therefore emerges as a hitherto unexpected link between macropinocytosis, actomyosin cytoskeleton organization, and DC migration.

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