CCDC134 controls TLR biogenesis through the ER chaperone Gp96.

Toll-like receptors (TLRs) are central to initiate immune responses against invading pathogens. To ensure host defense while avoiding aberrant activation leading to pathogenic inflammation and autoimmune diseases, TLRs are tightly controlled by multilevel regulatory mechanisms. Through a loss-of-function genetic screen in a reporter cell line engineered to undergo cell death upon TLR7-induced IRF5 activation, we identified here CCDC134 as an essential factor for TLR responses.

A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity.

Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular network involved, the identification of pathway- and disease-specific therapeutics has been challenging. Using a phenotypic assay monitoring the degradation of the immune adapter TASL, we identify feeblin, a chemical entity which inhibits the nucleic acid-sensing TLR7/8 pathway activating IRF5 by disrupting the SLC15A4-TASL adapter module.

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

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.