SLC15A3

SLC15A3 is a proton-coupled, lysosomal-membrane peptide/histidine transporter that doubles as a signaling scaffold in innate immune macrophages (PMID:24754256, PMID:31254495, PMID:30069489). It resides in the lysosomal membrane, co-localizing with LAMP1 (PMID:24754256), and a cryo-EM structure captures each protomer in an outward-facing state poised for substrate recognition (PMID:39719710). Functionally it transports free L-histidine with high affinity (Km ~67 μM) and dipeptides/peptidomimetics including Gly-Sar, valacyclovir, cefadroxil, and carnosine in a proton-coupled manner maximal at pH 5.5 (PMID:31254495, PMID:31073693). SLC15A3 expression is strongly induced during inflammation: multiple TLR ligands (TLR2/4/7/9) drive transcription through NF-κB, MAPK, and IRF3, with NF-κB (p65) and HIF1α binding directly to the promoter, and m6A RNA modification by METTL3/ALKBH5 adds post-transcriptional control (PMID:24754256, PMID:29991810, PMID:38717559, PMID:40679079). Once induced, SLC15A3 acts as a positive regulator of antiviral and inflammatory signaling: it interacts with MAVS and STING to potentiate type I/III interferon responses and restrict HSV-1 replication (PMID:30069489), enhances TASL recruitment to augment IRF5-driven M1 macrophage polarization (PMID:40679079), and binds the scaffold protein p62 to modulate the p62–NRF2 antioxidant/ROS axis, with its loss protecting mice from bleomycin- or radiation-induced pulmonary fibrosis (PMID:38374230).

1. 2014 Medium

   Established where SLC15A3 acts and that its expression is inflammation-responsive, framing it as an endolysosomal protein engaged during innate immunity.

   Evidence LAMP1 co-localization by confocal microscopy in HEK293 cells, and NF-κB-inhibitor-sensitive LPS induction in THP-1 macrophages and mouse spleen

   PMID:24754256

   Open questions at the time

   • Did not define transported substrates or transport mechanism
   • Single-cell-type localization without endogenous protein imaging
2. 2018 Medium

   Showed SLC15A3 is a broadly TLR-inducible gene with a functional role in shaping macrophage inflammatory output, moving it from passive transporter to immune effector.

   Evidence Reporter gene assays mapping NF-κB promoter sites, pathway inhibition, and knockdown/overexpression cytokine readouts in macrophages

   PMID:29991810

   Open questions at the time

   • Mechanistic link between transport activity and cytokine modulation not resolved
   • Relative contributions of NF-κB vs MAPK vs IRF3 not dissected
3. 2018 Medium

   Identified SLC15A3 as a scaffold for antiviral adaptors, demonstrating a signaling role beyond transport.

   Evidence Co-IP showing MAVS and STING interaction plus overexpression/knockdown effects on IFN production and HSV-1 replication in 293T cells

   PMID:30069489

   Open questions at the time

   • Single Co-IP without reciprocal or endogenous validation
   • Whether transport activity is required for IFN potentiation untested
4. 2019 High

   Defined the biochemical identity of SLC15A3 as a proton-coupled histidine/peptide transporter with a quantitative substrate profile.

   Evidence In vitro transport assays in MDCK cells with membrane-targeted hPHT2, Km determination and substrate/non-substrate profiling; carnosine uptake by knockdown and competitive inhibition in glioblastoma cells

   PMID:31073693 PMID:31254495

   Open questions at the time

   • Physiological substrate flux at the native lysosomal membrane not measured
   • Link between substrate transport and immune signaling not established
5. 2024 High

   Provided the structural basis for substrate recognition by capturing the transporter's conformational state.

   Evidence Cryo-EM structure of apo SLC15A3 showing outward-facing protomers

   PMID:39719710

   Open questions at the time

   • Substrate-bound and inward-facing states not resolved
   • Structural elements coupling transport to protein-protein interactions undefined
6. 2024 Medium

   Connected SLC15A3 to redox control via the p62–NRF2 axis and demonstrated a disease-relevant phenotype in vivo.

   Evidence Co-IP of SLC15A3–p62, SLC15A3 knockout mice, ROS measurement, and western blot of p62/NRF2 in fibrosis models

   PMID:38374230

   Open questions at the time

   • Single Co-IP for the p62 interaction
   • How transporter activity feeds into p62 phosphorylation not mechanistically resolved
7. 2024 Medium

   Identified the transcription factors directly driving SLC15A3 induction, refining the upstream regulatory logic.

   Evidence Luciferase reporter, siRNA, pharmacological inhibition, and chromatin binding for p65 and HIF1α in LPS/OGD-induced BV2 and NIH 3T3 cells

   PMID:38717559

   Open questions at the time

   • Cooperativity or hierarchy between p65 and HIF1α unresolved
   • Generalizability beyond microglial/fibroblast contexts untested
8. 2025 Medium

   Placed SLC15A3 in a TASL–IRF5 macrophage polarization axis under m6A post-transcriptional control, linking RNA modification to inflammatory cell fate.

   Evidence Conditional Mettl3/Alkbh5 knockout mice, polarization assays, and epistasis linking m6A → SLC15A3 → TASL–IRF5 in psoriasis models

   PMID:40679079

   Open questions at the time

   • Direct SLC15A3–TASL physical interaction not shown by structure or reciprocal Co-IP
   • Whether transport function is needed for TASL recruitment unknown

• How SLC15A3's transport activity is mechanistically coupled to its scaffolding of MAVS/STING, TASL, and p62 remains unresolved.
• No experiment separates transport-dead mutants from signaling competence
• No structure of SLC15A3 bound to any signaling partner
• Endogenous stoichiometry of these interactions in primary macrophages unknown