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

Abstract

Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses 1 – 3 . Here we show that a previously uncharacterized protein encoded by CXorf21 —a gene that is associated with systemic lupus erythematosus 4 , 5 —interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease 4 , 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 TRIF 10 , 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 erythematosus 12 – 14 .

Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import

“…Despite the high degree of functional redundancy displayed by transporters 46 , we show here that informative patterns of genetic interactions can be systematically derived for this family, allowing the generation of testable hypotheses for the de-orphanization of poorly characterized SLCs. Of all approaches that we have used in the past, including proteomics 47,48 , drug resistance 16,49 , and cell biological readouts 50,51 , genetic interactions among SLC has the potential to be one of the most powerful, as data points contribute to construct the evidence. As in a puzzle with a limited set of pieces, if all components are evaluated, individual genes may become implicated by exclusion principles.…”

Immune Sensing Mechanisms that Discriminate Self from Altered Self and Foreign Nucleic Acids

“…In human monocytes, TLR8 activation leads to the release of IFN-β and proinflammatory cytokines, including IL12p70, IL6, and TNF ( Bergstrøm et al., 2015 ; Cushing et al., 2017 ). Very recently, the type-I-interferon-inducible TLR adaptor interacting with SLC15A4 on the lysosome (TASL) has been reported as an additional signaling component linking endolysosomal TLR7 and TLR8 to interferon regulatory factor-5 (IRF5) and IFN-β induction ( Heinz et al., 2020 ). TASL recruits and activates IRF5, and loss of TASL specifically impairs the activation of the IRF pathway without affecting NF-κB and MAPK signaling, revealing a mechanistic analogy with STING, MAVS, and TRIF.…”

“…Whereas, in the mouse, TLR9 is widely expressed in immune cells, including myeloid cells, in humans, it is restricted to B cells and pDC ( Barchet et al., 2008 ), and their downstream immune effects differ accordingly. Notably, TASL was recently identified as an additional signaling protein linking TLR9 to IRF5 ( Heinz et al., 2020 ).…”

Macrophage imaging and subset analysis using single-cell RNA sequencing

“…Other SLC15 family members have also been examined as carriers of prodrugs including valacyclovir 136 . In myeloid cells SLC15A4 has been implicated in endolysosomal toll-like receptor (TLR) signaling, autoimmune disease, and downstream activation of the interferon regulatory factor 5 (IRF5) transcription factor which controls MΦ activation 137 .…”