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Title: BAD-LAMP controls TLR9 trafficking and signalling in human plasmacytoid dendritic cells
Author: Combes, Alexis
Camosseto, Voahirana
N'Guessan, Prudence
Argüello, Rafael J.
Mussard, Julie
Caux, Christophe
Bendriss-Vermare, Nathalie
Pierre, Philippe
Gatti, Evelina
Keywords: Cell Line, Tumor
Cells, Cultured
Dendritic Cells
Interferon Type I
Lysosomal-Associated Membrane Protein 2
Lysosome-Associated Membrane Glycoproteins
Microscopy, Confocal
NF-kappa B
Protein Transport
RNA Interference
Toll-Like Receptor 9
Transforming Growth Factor beta
Vesicle-Associated Membrane Protein 3
Signal Transduction
Issue Date: 13-Oct-2017
Publisher: Nature Research
Abstract: Toll-like receptors (TLR) are essential components of the innate immune system. Several accessory proteins, such as UNC93B1, are required for transport and activation of nucleic acid sensing Toll-like receptors in endosomes. Here, we show that BAD-LAMP (LAMP5) controls TLR9 trafficking to LAMP1+ late endosomes in human plasmacytoid dendritic cells (pDC), leading to NF-κB activation and TNF production upon DNA detection. An inducible VAMP3+/LAMP2+/LAMP1- endolysosome compartment exists in pDCs from which TLR9 activation triggers type I interferon expression. BAD-LAMP-silencing enhances TLR9 retention in this compartment and consequent downstream signalling events. Conversely, sustained BAD-LAMP expression in pDCs contributes to their lack of type I interferon production after exposure to a TGF-β-positive microenvironment or isolation from human breast tumours. Hence, BAD-LAMP limits interferon expression in pDCs indirectly, by promoting TLR9 sorting to late endosome compartments at steady state and in response to immunomodulatory cues.TLR9 is highly expressed by plasmacytoid dendritic cells and detects nucleic acids, but to discriminate between host and microbial nucleic acids TLR9 is sorted into different endosomal compartments. Here the authors show that BAD-LAMP limits type 1 interferon responses by sorting TLR9 to late endosomal compartments.
Peer review: yes
DOI: 10.1038/s41467-017-00695-1
Appears in Collections:IBIMED - Artigos

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