Gene

TLR3

Toll-like receptor

Cell biology

Pattern recognition receptor

Biology

Interferon regulatory factors

Receptor

Signal transducing adaptor protein

Signal transduction

DNA methylation

Computational biology

IRF3

Immunology

Genetics

TRIF

Immune system

Transcription factor

TLR7

Innate immune system

TLR9

Gene expression

IRF5

Nature

Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses1–3. Here we show that a previously uncharacterized protein encoded by CXorf21—a gene that is associated with systemic lupus erythematosus4,5—interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease4,6–9. 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 TRIF10,11. 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 erythematosus12–14. The interaction between TASL and SLC15A4 links endolysosomal Toll-like receptors to the transcription factor IRF5, providing a mechanistic explanation for the involvement of the complex in systemic lupus erythematosus.

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