The SLC15A4-LAMTOR1 interaction licenses endolysosomal TLR-mediated mTOR signaling and inflammatory cytokine production

Endolysosomal Toll-like receptors (TLRs) 7-9 are critical mediators of antimicrobial immunity, but their dysregulation drives pathogenic inflammation in autoimmune diseases such as systemic lupus erythematosus (SLE). The endolysosomal solute carrier SLC15A4 is essential for TLR7-9-mediated cytokine production and is strongly linked to SLE susceptibility, yet our understanding of the precise mechanisms by which it coordinates innate immune signaling remains incomplete. Here, we identify a direct interaction between SLC15A4 and LAMTOR1, a core scaffold subunit of the lysosomal Ragulator complex, and show that is required for coupling endolysosomal TLR activation to mTORC1 and downstream inflammatory responses. Structural modeling and site-directed mutagenesis suggest that the 1 helix of LAMTOR1 engages the substrate-binding pocket of SLC15A4, and disruption of this interface broadly suppresses TLR7-9-mediated cytokine production. Notably, this interaction regulates mTOR activation, IRF5/7 signaling, and downstream transcriptional responses through stimulus-dependent mechanisms. These findings define a previously uncharacterized SLC15A4-LAMTOR1 signaling interface that coordinates endolysosomal TLR-mTOR coupling and shapes downstream cytokine output. Significance StatementDysregulated activation of endolysosomal Toll-like receptors (TLRs) 7-9 drives pathogenic inflammatory cytokine responses that underlie autoimmune diseases such as systemic lupus erythematosus. Despite the established role of the endolysosomal transporter SLC15A4 in this process, how it coordinates downstream immune signaling has remained incompletely understood. We show that SLC15A4 directly interacts with LAMTOR1, a core component of the lysosomal Ragulator complex, and that this interaction is required to activate mTOR and engage IRF5/7-dependent inflammatory programs downstream of TLR7-9. Disrupting this interface suppresses type I interferon and cytokine production, identifying the SLC15A4-LAMTOR1 interaction as a central node in endolysosomal innate immune signaling and validating it as a compelling target for therapeutic intervention in interferon-driven autoimmune disease.