SLC66A1

SLC66A1 (PQLC2) is a lysosomal membrane transporter that exports cationic amino acids—arginine, lysine, and histidine—from the lysosomal lumen to the cytosol, functioning in lysosomal amino acid homeostasis and signaling (PMID:23169667). Biophysically it operates as a uniporter uncoupled from the lysosomal proton gradient, enabling bidirectional flux, with arginine uniquely acting as both substrate and inhibitor by binding and closing the cytosolic gate (PMID:34344826). Beyond transport, PQLC2 acts as a transceptor: an inward-facing conformation favored by low cationic amino acid availability presents a cavity that engages a flexible loop motif of WDR41, thereby recruiting the C9orf72–SMCR8–WDR41 complex to lysosomes and coupling lysosomal amino acid status to downstream signaling (PMID:31851326, PMID:33597295). Consistent with this signaling role, loss of PQLC2 drives TFEB nuclear translocation, impairs lysosomal mTORC1 recruitment and signaling, and disrupts lysosomal acidification, cathepsin activity, and autophagic flux (PMID:42172896). Delivery of PQLC2 to the lysosomal membrane depends on the AP-3 adaptor complex (PMID:26577948). The transporter function is evolutionarily conserved, with the C. elegans ortholog LAAT-1 mediating lysosomal lysine/arginine export and acting downstream of the cysteamine–cystine intermediate in cystine clearance (PMID:22822152).

1. 2012 High

   Established the core molecular identity of PQLC2 as a lysosomal exporter selective for cationic amino acids, answering what this orphan transporter does.

   Evidence Lysosomal patch-clamp electrophysiology, yeast complementation of the ypq2 mutant, and siRNA knockdown in cystinotic cells

   PMID:23169667

   Open questions at the time

   • Coupling mechanism to the proton gradient not yet resolved
   • Physiological consequences of transport in mammals not addressed
2. 2012 High

   Demonstrated in vivo physiological importance of the transporter ortholog by showing LAAT-1 loss causes lysosomal lysine/arginine accumulation and links it to cystine clearance, placing it in a defined degradation pathway.

   Evidence C. elegans genetics, lysosomal amino acid measurements, and epistasis with ctns-1 mutants

   PMID:22822152

   Open questions at the time

   • Mammalian relevance of the cystine-clearance role not directly tested
   • Transport directionality in the worm not biophysically characterized
3. 2015 Medium

   Resolved how PQLC2 reaches its site of action, identifying AP-3-dependent trafficking as the route to the lysosomal/vacuolar membrane.

   Evidence Yeast AP-3 mutant strains and siRNA knockdown of an AP-3 subunit in HeLa cells with fluorescence microscopy

   PMID:26577948

   Open questions at the time

   • Specific sorting signal in PQLC2 recognized by AP-3 not mapped
   • Single lab; reciprocal validation limited
4. 2019 Low

   Implicated PQLC2 in oncogenic growth signaling, raising the question of a transport-independent or downstream signaling role.

   Evidence Overexpression/knockdown in gastric cancer cells with MEK/ERK and PI3K/AKT western blots, colony formation, and mouse xenografts

   PMID:30729615

   Open questions at the time

   • Correlative pathway activation without direct biochemical linkage to transport function
   • Mechanism connecting transport to MEK/ERK and PI3K/AKT unresolved
5. 2020 High

   Defined PQLC2 as an amino acid sensor by showing it directly binds WDR41 and recruits the C9orf72 complex to lysosomes in a manner negatively regulated by its own substrates.

   Evidence Reciprocal co-immunoprecipitation, lysosomal fractionation, and amino acid supplementation/starvation with PQLC2 knockdown/overexpression

   PMID:31851326

   Open questions at the time

   • Downstream signaling output of recruited C9orf72 complex not defined here
   • Structural basis of substrate-regulated binding not established at this stage
6. 2020 Medium

   Showed nitrogen availability regulates the homolog's export activity, indicating nutrient-state control of cationic amino acid efflux.

   Evidence Yeast genetics with vacuolar arginine measurements under nitrogen shift

   PMID:32776922

   Open questions at the time

   • Whether mammalian PQLC2 is regulated analogously not tested
   • Molecular signal coupling nitrogen state to transport unknown
7. 2020 Low

   Linked PQLC2 to insulin signaling and glucose metabolism, suggesting roles beyond lysosomal amino acid export.

   Evidence siRNA knockdown in HepG2 cells with glucose uptake assay, GLUT2 qRT-PCR, and Akt phosphorylation western blot

   PMID:33051888

   Open questions at the time

   • Single knockdown approach; mechanism unresolved
   • Connection to transport or transceptor function not established
8. 2021 High

   Defined the biophysical transport mechanism as proton-uncoupled uniport and uncovered arginine's gate-tuning inhibitory mode, explaining how substrate identity shapes transport behavior.

   Evidence Lysosomal patch-clamp with reversal potential, charge/substrate ratio, intracellular pH measurements, and kinetic modeling

   PMID:34344826

   Open questions at the time

   • Atomic structures of conformational states not determined
   • Physiological consequence of arginine self-inhibition in vivo untested
9. 2021 High

   Provided the structural-conformational basis for transceptor function, showing a WDR41 loop motif inserts into the inward-facing PQLC2 cavity and that transport-related conformational changes gate complex recruitment.

   Evidence Mutagenesis of WDR41 loop and PQLC2 cavity residues, co-immunoprecipitation, lysosomal recruitment assays, and conformational trapping

   PMID:33597295

   Open questions at the time

   • High-resolution structure of the PQLC2–WDR41 complex not solved
   • Kinetics coupling transport cycle to recruitment not quantified
10. 2021 Medium

    Validated PQLC2-dependent cationic amino acid transport at single-organelle resolution, confirming the functional readout in individual lysosomes.

    Evidence Single-lysosome mass spectrometry combined with lysosomal patch-clamp

    PMID:34127857

    Open questions at the time

    • Novel method; broader replication limited
    • Does not address transceptor signaling
11. 2025 Low

    Identified a non-canonical requirement for PQLC2 in targeted EGFR degradation through the endolysosomal pathway.

    Evidence CRISPR/Cas9 genetic screen with morphological profiling of BiDAC-induced EGFR degradation

    PMID:40346034

    Open questions at the time

    • Mechanism not biochemically resolved
    • Whether the role depends on transport or transceptor activity unknown
12. 2026 Medium

    Tied PQLC2 loss directly to lysosomal signaling dysfunction, demonstrating consequences for TFEB, mTORC1, acidification, and autophagic flux.

    Evidence PQLC2 knockdown and knockout cell models with TFEB translocation, mTORC1 recruitment, cathepsin activity, lysosomal pH, and autophagy flux assays

    PMID:42172896

    Open questions at the time

    • Causal chain from transport/transceptor activity to acidification defect not dissected
    • Single lab
13. 2026 Low

    Showed upstream regulation of the ortholog's lysosomal/phagosomal recruitment by a neuropeptide signal during apoptotic cell clearance.

    Evidence C. elegans RNAi screen, LAAT-1::GFP recruitment microscopy, phagosomal acidification assay, and transcriptional reporter for INS-14 modulation

    PMID:41610718

    Open questions at the time

    • Indirect regulatory finding in worm ortholog
    • Mammalian conservation of neuropeptide control untested

• How PQLC2's transport activity, transceptor recruitment of the C9orf72 complex, and the broader signaling and disease-associated phenotypes are mechanistically unified remains unresolved.
• No atomic structure of PQLC2 or its complex with WDR41
• Mechanistic basis for reported insulin, oncogenic, and EGFR-degradation roles not biochemically tied to transport or transceptor function
• Direct link between PQLC2-mediated transport and the lysosomal acidification defect unestablished