TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9.

Details

Serval ID
serval:BIB_E5CFC01382DB
Type
Article: article from journal or magazin.
Collection
Publications
Title
TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9.
Journal
Nature
Author(s)
Heinz L.X., Lee J., Kapoor U., Kartnig F., Sedlyarov V., Papakostas K., César-Razquin A., Essletzbichler P., Goldmann U., Stefanovic A., Bigenzahn J.W., Scorzoni S., Pizzagalli M.D., Bensimon A., Müller A.C., King F.J., Li J., Girardi E., Mbow M.L., Whitehurst C.E., Rebsamen M., Superti-Furga G.
ISSN
1476-4687 (Electronic)
ISSN-L
0028-0836
Publication state
Published
Issued date
05/2020
Peer-reviewed
Oui
Volume
581
Number
7808
Pages
316-322
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses <sup>1-3</sup> . Here we show that a previously uncharacterized protein encoded by CXorf21-a gene that is associated with systemic lupus erythematosus <sup>4,5</sup> -interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease <sup>4,6-9</sup> . Loss of this type-I-interferon-inducible protein, which we refer to as 'TLR adaptor interacting with SLC15A4 on the lysosome' (TASL), abrogated responses to endolysosomal TLR agonists in both primary and transformed human immune cells. Deletion of SLC15A4 or TASL specifically impaired the activation of the IRF pathway without affecting NF-κB and MAPK signalling, which indicates that ligand recognition and TLR engagement in the endolysosome occurred normally. Extensive mutagenesis of TASL demonstrated that its localization and function relies on the interaction with SLC15A4. TASL contains a conserved pLxIS motif (in which p denotes a hydrophilic residue and x denotes any residue) that mediates the recruitment and activation of IRF5. This finding shows that TASL is an innate immune adaptor for TLR7, TLR8 and TLR9 signalling, revealing a clear mechanistic analogy with the IRF3 adaptors STING, MAVS and TRIF <sup>10,11</sup> . The identification of TASL as the component that links endolysosomal TLRs to the IRF5 transcription factor via SLC15A4 provides a mechanistic explanation for the involvement of these proteins in systemic lupus erythematosus <sup>12-14</sup> .
Keywords
Amino Acid Motifs, Animals, Female, Humans, Immunity, Innate, Interferon Regulatory Factors/metabolism, Interferon Type I/immunology, Intracellular Signaling Peptides and Proteins/chemistry, Intracellular Signaling Peptides and Proteins/deficiency, Intracellular Signaling Peptides and Proteins/genetics, Intracellular Signaling Peptides and Proteins/metabolism, Lupus Erythematosus, Systemic/metabolism, Lysosomes/metabolism, Male, Membrane Transport Proteins/deficiency, Membrane Transport Proteins/genetics, Membrane Transport Proteins/metabolism, Nerve Tissue Proteins/deficiency, Nerve Tissue Proteins/genetics, Nerve Tissue Proteins/metabolism, Protein Binding, Signal Transduction, Toll-Like Receptor 7/metabolism, Toll-Like Receptor 8/metabolism, Toll-Like Receptor 9/metabolism
Pubmed
Web of science
Create date
11/08/2020 16:06
Last modification date
13/08/2020 5:26
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