Affinage

SNX14

Sorting nexin-14 · UniProt Q9Y5W7

Length
946 aa
Mass
110.2 kDa
Annotated
2026-04-28
19 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNX14 is an ER-anchored sorting nexin that functions at membrane contact sites to coordinate lipid metabolism, organelle homeostasis, and membrane protein trafficking. Its N-terminal transmembrane helices anchor it in the ER, where it localizes to ER–lipid droplet contact sites to promote lipid droplet growth and maintain fatty acid saturation balance through functional interaction with the Δ-9 desaturase SCD1; loss of SNX14 causes saturated fatty acid–driven lipotoxicity, lysosomal cholesterol accumulation, and impaired autophagosome clearance (PMID:29635513, PMID:30765438, PMID:33310904, PMID:25848753). Through its RGS domain, SNX14 sequesters Gαs to inhibit cAMP signaling downstream of the 5-HT6 receptor and promotes receptor lysosomal degradation, while in neurons it stabilizes the microtubule-severing enzyme spastin to support axonal mitochondrial transport and also regulates GluA2 AMPA receptor levels via lysosomal degradation (PMID:25795301, PMID:34691693, PMID:40237949). Biallelic loss-of-function mutations in SNX14 cause spinocerebellar ataxia autosomal recessive 20 (SCAR20), driven by lipotoxic Purkinje cell degeneration characterized by acylcarnitine accumulation, triglyceride depletion, and telolysosome enlargement (PMID:25848753, PMID:38625743).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2014 Medium

    Establishing a neuronal role: SNX14 was shown to be required for normal synaptic transmission and intrinsic excitability in neurons, with expression increasing during neuronal maturation, revealing that this sorting nexin has a critical neuronal function beyond vesicle trafficking.

    Evidence shRNA knockdown in mouse neurons with electrophysiological recordings

    PMID:24859318

    Open questions at the time
    • Molecular target(s) mediating synaptic transmission effects not identified
    • Single lab without independent replication
    • Mechanism linking SNX14 loss to reduced excitability undefined
  2. 2015 High

    Linking SNX14 to endolysosomal function and disease: SNX14 was found to associate with PI(3,5)P2-positive late endosomes/lysosomes, and its loss caused lysosomal engorgement and impaired autophagosome clearance, directly connecting biallelic SNX14 mutations to SCAR20 cerebellar ataxia.

    Evidence Subcellular fractionation, lipid binding assays, patient-derived fibroblast autophagy flux, zebrafish morphant phenotyping

    PMID:25848753

    Open questions at the time
    • Mechanism by which SNX14 facilitates autophagosome–lysosome fusion was not defined
    • Whether the lysosomal phenotype is primary or secondary to ER lipid defects was unclear
  3. 2015 Medium

    Defining a GPCR signaling regulatory mechanism: SNX14 was shown to act as a dual negative regulator of 5-HT6R signaling—its RGS domain sequesters Gαs to suppress cAMP, while PKA-dependent phosphorylation of SNX14 switches it to promote 5-HT6R internalization and lysosomal degradation, establishing a feedback circuit.

    Evidence Reciprocal co-immunoprecipitation, cAMP measurement, receptor internalization assays, PKA phosphorylation assays, knockdown rescue in HEK293 cells

    PMID:25795301

    Open questions at the time
    • In vivo relevance of 5-HT6R regulation by SNX14 not tested
    • Whether RGS domain activity extends to other Gα subunits unknown
    • Single lab study
  4. 2018 High

    Redefining SNX14 as an ER-resident protein: domain mutagenesis established that N-terminal transmembrane helices (not the PX domain) anchor SNX14 to the ER, and SNX14 knockout caused cholesterol and neutral lipid accumulation in lysosomes without disrupting ER–endolysosome contact sites, shifting the primary functional assignment from endosome to ER.

    Evidence Domain deletion constructs, filipin staining, cholesterol ester quantification, oleate-induced LD association in SNX14-KO HEK293 cells

    PMID:29635513

    Open questions at the time
    • Structural basis of ER anchoring not resolved
    • Whether cholesterol accumulation is a direct lipid transport defect or secondary unclear
  5. 2019 High

    Establishing ER–lipid droplet contact site function: SNX14 was shown to localize to ER–LD contacts in trans following fatty acid treatment, accumulating at ACSL3-positive ER microdomains where nascent LDs bud, and promoting LD maturation/growth independently of Seipin.

    Evidence APEX2 proximity labeling, live imaging, topological dissection, KO morphology analysis in U2OS cells

    PMID:30765438

    Open questions at the time
    • Direct lipid transfer activity not demonstrated
    • Structural basis of LD binding in trans unknown
    • Whether SNX14 directly senses nascent LD budding or is passively recruited unclear
  6. 2020 High

    Connecting SNX14 to fatty acid desaturation and lipotoxicity: APEX2 proteomics identified SCD1 as a functional partner, and SNX14 loss phenocopied SCD1 impairment by increasing membrane lipid saturation and sensitizing cells to palmitate-induced lipotoxic death—a phenotype rescued by SCD1 overexpression—establishing lipotoxicity as the cellular pathomechanism in SCAR20.

    Evidence APEX2 proximity labeling, lipidomic profiling, SCD1 overexpression rescue, lipotoxicity assays in SNX14-KO and SCAR20 patient fibroblasts

    PMID:33310904

    Open questions at the time
    • Whether SNX14 directly modulates SCD1 enzymatic activity or substrate access unknown
    • Tissue-specific lipotoxic thresholds in Purkinje cells not quantified
  7. 2021 Medium

    Revealing a microtubule/mitochondrial transport role in neurodegeneration: SNX14 deficiency was found to destabilize spastin, disrupt microtubule organization and axonal mitochondrial transport in Purkinje cells, with valproate rescuing both mitochondrial transport and motor deficits in vivo, adding a cytoskeletal dimension to the SCAR20 mechanism.

    Evidence Snx14-deficient mouse model, spastin protein quantification, live axonal mitochondrial transport imaging, valproate treatment rescue

    PMID:34691693

    Open questions at the time
    • Mechanism by which SNX14 stabilizes spastin not defined
    • Whether spastin destabilization is a direct interaction or mediated by lipid changes unknown
    • Single lab
  8. 2024 Medium

    Validating lipotoxicity as the in vivo Purkinje cell death mechanism: lipidomic and ultrastructural analysis of predegenerating SNX14-deficient cerebella revealed acylcarnitine accumulation, triglyceride depletion, LD content defects, and telolysosome enlargement, confirming that lipid storage failure precedes neurodegeneration.

    Evidence SNX14-deficient mouse cerebella, electron microscopy, lipidomic profiling, immunohistochemistry

    PMID:38625743

    Open questions at the time
    • Causal chain from lipid storage defect to Purkinje cell death not fully delineated
    • Contribution of lysosomal versus ER dysfunction not resolved in vivo
    • Single lab
  9. 2025 Medium

    Identifying GluA2 as a neuronal substrate: SNX14 was shown to promote lysosomal degradation of the AMPA receptor subunit GluA2, thereby regulating glutamatergic transmission and seizure susceptibility, expanding its membrane protein trafficking repertoire beyond 5-HT6R.

    Evidence SNX14 knockdown and overexpression in mouse hippocampus, GluA2 western blotting, lysosomal inhibition, seizure behavioral assays

    PMID:40237949

    Open questions at the time
    • Whether SNX14 directly binds GluA2 not shown
    • Mechanism of cargo selectivity for GluA2 versus other receptors unknown
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether SNX14 directly transfers lipids at ER–LD contacts, how it mechanistically couples to SCD1 activity, the structural basis of its multi-site membrane engagement, and whether lipotoxicity and cytoskeletal defects represent parallel or convergent pathogenic pathways in SCAR20.
  • No direct lipid transfer activity demonstrated
  • No high-resolution structure of SNX14
  • Relative contributions of lipotoxicity versus spastin/microtubule defects to Purkinje cell death unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005811 lipid droplet 3 GO:0005764 lysosome 2
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-112316 Neuronal System 2 R-HSA-9612973 Autophagy 2 R-HSA-162582 Signal Transduction 1
Partners
ACSL3GNASGRIA2HTR6SCD1SPAST

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 SNX14 localizes to lysosomes and associates with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes; loss of SNX14 causes engorged lysosomes and slower autophagosome clearance upon starvation-induced autophagy Subcellular fractionation/localization, patient-derived cell autophagy flux assays, zebrafish morphant accumulation of autophagosomes Nature genetics High 25848753
2014 SNX14 knockdown in neurons reduces intrinsic excitability and severely impairs both excitatory and inhibitory synaptic transmission; SNX14 protein levels increase progressively during neuronal development and maturation Knockdown (shRNA/siRNA) with electrophysiological readouts in mouse neurons; laser capture microdissection for imprinting analysis PloS one Medium 24859318
2015 SNX14 directly interacts with the serotonin 5-HT6 receptor and promotes its internalization and lysosomal degradation; the RGS domain of SNX14 binds and sequesters Gαs to inhibit cAMP production; PKA-mediated phosphorylation of SNX14 inhibits Gαs binding and redirects SNX14 to promote 5-HT6R endocytic degradation Co-immunoprecipitation, receptor internalization assays, cAMP measurement, PKA phosphorylation assay, knockdown rescue experiments Journal of cell science Medium 25795301
2018 SNX14 is an ER-resident protein requiring its N-terminal transmembrane helices for ER localization (PX domain is dispensable for localization); SNX14 loss causes cholesterol accumulation in LAMP1-positive lysosomal structures and perturbed neutral lipid metabolism; SNX14 associates with ER-derived lipid droplets following oleate treatment; ER-late endosome/lysosome contact sites are maintained in SNX14KO cells, indicating SNX14 is not required for ER-endolysosomal tethering Domain deletion/mutagenesis for localization, filipin staining, cholesterol ester measurement, oleate treatment LD association, SNX14KO HEK293 cells Human molecular genetics High 29635513
2019 Snx14 is an ER-resident protein that localizes to ER-lipid droplet (ER-LD) contact sites following fatty acid treatment, where it promotes LD maturation/growth while remaining ER-anchored and binding LDs in trans; Snx14 accumulates at ER microdomains containing the fatty acyl-CoA ligase ACSL3 where nascent LDs bud; Snx14 localization to ER-LD contacts is independent of Seipin APEX2 proximity labeling, live imaging, topological dissection, Snx14 KO morphology analysis, multi-time point imaging, co-localization with ACSL3 The Journal of cell biology High 30765438
2020 Snx14 functions as an ER-LD tethering protein required to maintain lipid saturation balance; SNX14KO cells show ER integrity compromise and hypersensitivity to saturated fatty acid-mediated lipotoxic cell death; APEX2 proximity labeling reveals functional interaction between Snx14 and Δ-9 FA desaturase SCD1; SNX14KO cells increase membrane lipid saturation following palmitate exposure, phenocopying SCD1-impaired cells; lipotoxicity in SNX14KO cells can be rescued by SCD1 overexpression APEX2 proximity labeling, lipidomic profiling, SCD1 overexpression rescue, lipotoxicity assays in SNX14KO and SCAR20 patient-derived cells Proceedings of the National Academy of Sciences of the United States of America High 33310904
2021 SNX14 deficiency destabilizes the microtubule-severing enzyme spastin, disrupts microtubule organization and axonal mitochondrial transport in Purkinje cells, leading to compromised axonal integrity and mitochondrial dysfunction; the antiepileptic drug valproate restores mitochondrial transport and function and ameliorates motor deficits in Snx14-deficient mice Snx14-deficient mouse model, motor behavior tests, spastin protein level analysis, live axonal mitochondrial transport imaging, valproate treatment rescue National science review Medium 34691693
2021 Yeast Mdm1 (SNX14 ortholog) at the nucleus-vacuole junction (NVJ) mediates TORC1 inactivation-induced nucleolar protein migration and proper nucleophagic degradation of nucleolar proteins, while being dispensable for the induction of nucleophagic flux itself Genetic deletion of Mdm1 in yeast, fluorescence microscopy of nucleolar dynamics, nucleophagic flux assays under nutrient starvation Biochemical and biophysical research communications Medium 33740659
2024 SNX14-deficient Purkinje cells show lipid storage and metabolism defects including accumulation of acylcarnitines and depletion of triglycerides in predegenerating cerebella; lipid droplet content defects and telolysosome enlargement suggest lipotoxicity as the pathogenic mechanism of SNX14 deficiency-driven Purkinje cell neurodegeneration SNX14-deficient mouse model, ultrastructural analysis (electron microscopy), lipidomic profiling, immunohistochemistry for Purkinje cell markers JCI insight Medium 38625743
2025 SNX14 regulates GluA2 (AMPA receptor subunit) protein levels by promoting GluA2 degradation via the lysosomal pathway, thereby influencing glutamatergic synaptic transmission; SNX14 knockdown in hippocampus decreases seizure susceptibility while overexpression increases it SNX14 knockdown and overexpression in mouse hippocampus, western blotting for GluA2, lysosomal inhibition assays, seizure susceptibility behavioral assays Molecular neurobiology Medium 40237949

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction. Nature genetics 103 25848753
2019 Cerebellar ataxia disease-associated Snx14 promotes lipid droplet growth at ER-droplet contacts. The Journal of cell biology 95 30765438
2014 Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome. American journal of human genetics 85 25439728
2018 SNX14 mutations affect endoplasmic reticulum-associated neutral lipid metabolism in autosomal recessive spinocerebellar ataxia 20. Human molecular genetics 56 29635513
2014 Snx14 regulates neuronal excitability, promotes synaptic transmission, and is imprinted in the brain of mice. PloS one 33 24859318
2015 SNX14 is a bifunctional negative regulator for neuronal 5-HT6 receptor signaling. Journal of cell science 28 25795301
2023 Apoptotic Vesicles Regulate Bone Metabolism via the miR1324/SNX14/SMAD1/5 Signaling Axis. Small (Weinheim an der Bergstrasse, Germany) 25 36670083
2021 SNX14 deficiency-induced defective axonal mitochondrial transport in Purkinje cells underlies cerebellar ataxia and can be reversed by valproate. National science review 20 34691693
2016 Genome sequencing reveals a splice donor site mutation in the SNX14 gene associated with a novel cerebellar cortical degeneration in the Hungarian Vizsla dog breed. BMC genetics 20 27566131
2020 Snx14 proximity labeling reveals a role in saturated fatty acid metabolism and ER homeostasis defective in SCAR20 disease. Proceedings of the National Academy of Sciences of the United States of America 18 33310904
2024 Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency. JCI insight 8 38625743
2021 Sorting nexin Mdm1/SNX14 regulates nucleolar dynamics at the NVJ after TORC1 inactivation. Biochemical and biophysical research communications 6 33740659
2020 Two Compound Heterozygous Variants in SNX14 Cause Stereotypies and Dystonia in Autosomal Recessive Spinocerebellar Ataxia 20. Frontiers in genetics 5 33193593
2024 SNX14 inhibits autophagy via the PI3K/AKT/mTOR signaling cascade in breast cancer cells. Journal of molecular histology 4 38869753
2023 Homozygous deep intronic variant in SNX14 cause autosomal recessive Spinocerebellar ataxia 20: a case report. Frontiers in genetics 4 37485342
2022 Autosomal recessive spinocerebellar ataxia-20 due to a novel SNX14 variant in an Indian girl. American journal of medical genetics. Part A 3 35195341
2025 Inhibiting SNX14 Alleviates Epileptic Seizures by Regulating GluA2 Degradation via the Lysosomal Pathway. Molecular neurobiology 1 40237949
2024 Compound heterozygous mutation of the SNX14 gene causes autosomal recessive spinocerebellar ataxia 20. Frontiers in genetics 1 38655056
2025 Exploring the Genetic Variations Underlying SNX14-Linked Autosomal Recessive Spinocerebellar Ataxia Type 20: A Case Series of 17 Patients From a Single Center in the Omani Population and Review of Literature. American journal of medical genetics. Part A 0 41294032