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

Leonhard X. Heinz, JangEun Lee, Utkarsh Kapoor, Felix Kartnig, Vitaly Sedlyarov, Konstantinos Papakostas, Adrian César-Razquin, Patrick Essletzbichler, Ulrich Goldmann, Adrijana Stefanovic, Johannes W. Bigenzahn, Stefania Scorzoni, Mattia D. Pizzagalli, Ariel Bensimon, André C. Müller, F. James King, Jun Li, Enrico Girardi, M. Lamine Mbow, Charles E. Whitehurst, Manuele Rebsamen () and Giulio Superti-Furga ()
Additional contact information
Leonhard X. Heinz: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
JangEun Lee: Boehringer Ingelheim Pharmaceuticals
Utkarsh Kapoor: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Felix Kartnig: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Vitaly Sedlyarov: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Konstantinos Papakostas: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Adrian César-Razquin: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Patrick Essletzbichler: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Ulrich Goldmann: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Adrijana Stefanovic: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Johannes W. Bigenzahn: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Stefania Scorzoni: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Mattia D. Pizzagalli: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Ariel Bensimon: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
André C. Müller: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
F. James King: Boehringer Ingelheim Pharmaceuticals
Jun Li: Boehringer Ingelheim Pharmaceuticals
Enrico Girardi: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
M. Lamine Mbow: Boehringer Ingelheim Pharmaceuticals
Charles E. Whitehurst: Boehringer Ingelheim Pharmaceuticals
Manuele Rebsamen: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Giulio Superti-Furga: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences

Nature, 2020, vol. 581, issue 7808, 316-322

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-2282-0

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