SLC22A13

SLC22A13 (OAT10/ORCTL3) is a polytopic plasma-membrane organic-anion transporter of the organic-cation transporter family, expressed prominently in kidney where it serves dual transport roles defined by membrane polarity (PMID:10072596, PMID:24147638, PMID:35462902). At the apical membrane of renal proximal tubular cells it reabsorbs urate from urine; carriers of the dysfunctional p.R377C variant show lower serum urate and elevated fractional uric-acid excretion, and the uricosuric drugs losartan and lesinurad inhibit OAT10, accounting for part of their urate-lowering action (PMID:35462902). The independent loss-of-function variant p.R16H further confirms its role in urate transport by reducing activity without altering protein levels or membrane localization (PMID:38222853). At the basolateral membrane of type A intercalated cells it co-localizes with anion exchanger 1 and catalyzes unidirectional efflux of aspartate, glutamate, taurine, and guanidinosuccinate (PMID:24147638). OAT10 physically associates with the monocarboxylate transporter MCT1 (SLC16A1), which provides an efflux escape route for shared substrates and thereby shapes the transporter's apparent substrate selectivity (PMID:35926947). Independent of transport function, ORCTL3 selectively triggers apoptosis in oncogene-transformed cells but not normal cells by inhibiting stearoyl-CoA desaturase-1 (SCD1) through its transmembrane domains 3 and 4, an effect engaging an ER-stress pathway and rescuable by the SCD1 product oleic acid; adenoviral ORCTL3 suppresses renal tumor growth in vivo and ex vivo (PMID:19282870, PMID:24769897).

1. 1998 Medium

   Established SLC22A13 as a distinct organic-cation-transporter-family gene with a defined chromosomal locus and expression pattern, providing the molecular entry point before any function was known.

   Evidence Genomic sequencing, molecular cloning, homology analysis and tissue expression profiling

   PMID:10072596

   Open questions at the time

   • No transport substrate or activity demonstrated
   • Subcellular localization unresolved
   • Physiological role inferred only from family homology
2. 2009 Medium

   Revealed an unexpected transport-independent role in selectively killing transformed cells via ER stress, distinguishing a tumor-specific pro-apoptotic function from any transporter activity.

   Evidence cDNA synthetic-lethal screen in isogenic normal vs transformed cells with ATF4/BiP ER-stress marker analysis

   PMID:19282870

   Open questions at the time

   • Molecular target of apoptotic activity not identified
   • Mechanism linking ORCTL3 to ER stress undefined
   • Single-lab observation
3. 2014 High

   Defined the first transport function and its membrane polarity, showing basolateral OAT10 in type A intercalated cells performs unidirectional efflux of acidic amino acids rather than bidirectional exchange.

   Evidence Immunohistochemistry with AE1 co-staining plus LC-MS and radiolabeled-substrate efflux/uptake assays in HEK-293 cells

   PMID:24147638

   Open questions at the time

   • Driving force / coupling ion of efflux not established
   • Relationship between this efflux role and apical urate role unaddressed
4. 2014 High

   Identified SCD1 in fatty-acid metabolism as the molecular target of ORCTL3's tumor-specific apoptosis and mapped the responsible transmembrane domains, converting the 2009 phenotype into a defined mechanism with therapeutic potential.

   Evidence SCD1 co-transfection and oleic-acid rescue, transmembrane-domain mutagenesis, in vivo xenograft and ex vivo patient tumor assays

   PMID:24769897

   Open questions at the time

   • Physical interaction between ORCTL3 TM3/4 and SCD1 not structurally resolved
   • How SCD1 inhibition triggers ER stress not detailed
5. 2022 High

   Established OAT10 as an apical renal urate reabsorber and a pharmacological target, linking a human dysfunctional variant to lower serum urate and explaining uricosuric drug action.

   Evidence QTL analysis (n=4,521), immunohistochemistry, functional transport and pharmacological inhibition assays in HEK293 cells

   PMID:35462902

   Open questions at the time

   • Quantitative contribution of OAT10 to total renal urate handling vs URAT1 not resolved
   • Counter-ion/exchange substrate for urate uptake unspecified
6. 2022 Medium

   Showed OAT10 physically partners with MCT1, with MCT1 serving as an efflux escape route that modulates OAT10's apparent substrate selectivity, adding a regulatory layer to its transport.

   Evidence Co-IP/LC-MS/MS interactome, MCT1 siRNA knockdown with substrate-specific transport readouts in oocytes and HEK293 cells

   PMID:35926947

   Open questions at the time

   • Stoichiometry and structural basis of OAT10-MCT1 interaction unknown
   • Physiological tissue context of the interaction not established
   • Single-lab finding
7. 2024 Medium

   Characterized a second loss-of-function urate-transport variant (p.R16H), reinforcing OAT10's role in urate handling by separating transport defect from protein expression/localization defects.

   Evidence Site-directed mutagenesis, functional transport assay, immunoblotting and fluorescence microscopy in HEK293A cells

   PMID:38222853

   Open questions at the time

   • Population-level clinical consequence of p.R16H not quantified
   • Mechanism by which R16H impairs transport not defined

• How OAT10's two membrane-polarized transport roles, its MCT1 partnership, and its transport-independent SCD1-targeting apoptotic activity are integrated within one protein remains unresolved.
• No structural model of substrate binding or domain architecture
• Coupling/energetics of urate and amino-acid transport unknown
• Whether apoptotic and transport functions occur in the same cellular contexts unaddressed