SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL

Haobo Zhang; Léa Bernaleau; Maeva Delacrétaz; Ed Hasanovic; Ales Drobek; Hermann Eibel; Manuele Rebsamen

doi:10.1016/j.celrep.2023.112916

SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL

Cell Rep. 2023 Aug 29;42(8):112916. doi: 10.1016/j.celrep.2023.112916. Epub 2023 Jul 31.

Authors

Haobo Zhang¹, Léa Bernaleau¹, Maeva Delacrétaz¹, Ed Hasanovic¹, Ales Drobek¹, Hermann Eibel², Manuele Rebsamen³

Affiliations

¹ Department of Immunobiology, University of Lausanne, Ch. des Boveresses 155, 1066 Epalinges, Switzerland.
² Department of Rheumatology and Clinical Immunology, Medical Center and Faculty of Medicine, University of Freiburg, Hugstetterstr. 55, 79106 Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, Breisacherstr. 115, 79106 Freiburg, Germany.
³ Department of Immunobiology, University of Lausanne, Ch. des Boveresses 155, 1066 Epalinges, Switzerland. Electronic address: manuele.rebsamen@unil.ch.

PMID: 37527038
DOI: 10.1016/j.celrep.2023.112916

Abstract

Endolysosomal Toll-like receptors (TLRs) play crucial roles in immune responses to pathogens, while aberrant activation of these pathways is associated with autoimmune diseases, including systemic lupus erythematosus (SLE). The endolysosomal solute carrier family 15 member 4 (SLC15A4) is required for TLR7/8/9-induced responses and disease development in SLE models. SLC15A4 has been proposed to affect TLR7-9 activation through its transport activity, as well as by assembling an IRF5-activating complex with TASL, but the relative contribution of these functions remains unclear. Here, we show that the essential role of SLC15A4 is to recruit TASL to endolysosomes, while its transport activity is dispensable when TASL is tethered to this compartment. Endolysosomal-localized TASL rescues TLR7-9-induced IRF5 activation as well as interferon β and cytokine production in SLC15A4-deficient cells. SLC15A4 acts as signaling scaffold, and this function is essential to control TLR7-9-mediated inflammatory responses. These findings support targeting the SLC15A4-TASL complex as a potential therapeutic strategy for SLE and related diseases.

Keywords: CP: Immunology; IRF5; SLC15A4; SLE; TASL; Toll-like receptors; autoimmunity; lysosome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Immunity, Innate
Interferon Regulatory Factors / metabolism
Lupus Erythematosus, Systemic*
Membrane Transport Proteins / metabolism
Nerve Tissue Proteins / metabolism
Toll-Like Receptor 7* / metabolism
Toll-Like Receptors / metabolism

Substances

Toll-Like Receptor 7
Toll-Like Receptors
Interferon Regulatory Factors
TLR7 protein, human
SLC15A4 protein, human
Nerve Tissue Proteins
Membrane Transport Proteins