SNX10

SNX10 is a PX-domain sorting nexin that functions as a central regulator of endosomal and lysosomal trafficking, controlling vesicle maturation, cargo sorting, and organelle acidification across multiple cell types. Through its PtdIns3P-binding PXe domain, SNX10 localizes to early endosomes where it recruits effectors including V-ATPase, PIKfyve, Mon1-Ccz1, CLC-7, and caspase-5 to direct phagosome maturation, autophagosome-lysosome fusion, chaperone-mediated autophagy via CTSA-dependent LAMP-2A turnover, piecemeal mitophagy, and receptor recycling through RAB11A (PMID:21844891, PMID:29452206, PMID:28903313, PMID:31692073, PMID:40052924, PMID:40228127, PMID:41408708). In osteoclasts, SNX10 targets V-ATPase and CLC-7/OSTM1-containing lysosomes to the ruffled border, enables proton secretion for bone resorption, and limits mature osteoclast fusion to maintain cell size; loss-of-function mutations including R51Q cause autosomal recessive osteopetrosis characterized by absent ruffled borders, defective acidification, and pathological osteoclast hyperfusion (PMID:22499339, PMID:25811986, PMID:32278070, PMID:39095084). In epithelial and immune cells, SNX10 recruits caspase-5 to endosomes for cytosolic LPS sensing, stabilizes LRP6 to support Wnt/β-catenin signaling, and regulates HER2 surface expression through RAB11A-dependent recycling (PMID:34747049, PMID:39603572, PMID:40228127).

1. 2011 High

   The discovery that SNX10 interacts with V-ATPase and directs it to the centrosome for ciliogenesis established SNX10 as an active trafficking adaptor rather than a passive endosomal binder, and linked it to ciliary biology and left-right patterning.

   Evidence Co-immunoprecipitation, confocal imaging of Rab8a, and zebrafish morpholino knockdown showing cilia loss in Kupffer's vesicle

   PMID:21844891

   Open questions at the time

   • Whether SNX10-V-ATPase interaction is direct or scaffold-mediated was not resolved
   • Structural basis of SNX10-V-ATPase recognition unknown
2. 2012 High

   Identification of SNX10 loss-of-function mutations in autosomal recessive osteopetrosis (ARO) patients, together with the demonstration that SNX10 knockdown blocks RANKL-induced osteoclast bone resorption, established SNX10 as essential for osteoclast function and linked it to a Mendelian skeletal disease.

   Evidence Homozygosity mapping in ARO families; patient osteoclast resorption and endocytosis assays; siRNA knockdown in cultured osteoclasts with resorption on hydroxyapatite

   PMID:22174188 PMID:22499339

   Open questions at the time

   • Precise cargo sorted by SNX10 to the ruffled border was not identified
   • Whether SNX10 mutations affect osteoclast differentiation or only function was debated
3. 2014 High

   Crystal structures of SNX10 (and the closely related SNX11) revealed the extended PXe domain architecture with two additional C-terminal α-helices, and mapped disease mutations (R51Q, Y32, R16L) to stability or interaction surfaces, providing the first structural framework for understanding SNX10 pathophysiology.

   Evidence X-ray crystallography at 2.6 Å; site-directed mutagenesis with vacuolation activity assays

   PMID:23615901 PMID:25212774

   Open questions at the time

   • No co-crystal structure with any binding partner
   • How PXe C-terminal helices mediate protein-protein interactions remained undefined
4. 2015 High

   Tissue-specific knockouts resolved that SNX10 functions cell-autonomously in osteoclasts for ruffled border formation and bone resorption, and independently in gastric epithelium for acid secretion and calcium solubilization, explaining the osteopetrorickets phenotype of global knockout.

   Evidence Global and osteoclast-specific Snx10 KO mice with bone histomorphometry, endocytosis and acidification assays, calcium supplementation rescue

   PMID:25811986

   Open questions at the time

   • Molecular identity of cargo sorted by SNX10 in gastric cells not determined
   • Whether SNX10 delivers V-ATPase or other acidification machinery in stomach was not tested directly
5. 2017 High

   Demonstration that SNX10 recruits the Mon1-Ccz1 complex to phagosomes for Rab7 activation and bacterial killing, and that R51Q knock-in mice recapitulate ARO with absent ruffled borders, extended SNX10's role from osteoclasts to innate immune phagosome maturation and validated the disease-causing mechanism in vivo.

   Evidence SNX10 KO macrophages with Mon1-Ccz1 recruitment and Listeria killing assays; R51Q knock-in mouse osteoclast TEM and proton secretion

   PMID:28592808 PMID:28903313

   Open questions at the time

   • Whether Mon1-Ccz1 recruitment is a direct SNX10 interaction or indirect was not resolved
   • Phagosome maturation role not tested outside macrophages
6. 2018 High

   The finding that SNX10 directly binds cathepsin A and controls its maturation, thereby regulating LAMP-2A stability and chaperone-mediated autophagy (CMA) activity, revealed a non-classical trafficking function connecting endosomal sorting to selective autophagy.

   Evidence Snx10 KO mice; pull-down assay confirming SNX10-CTSA interaction; LAMP-2A interference epistasis; CMA reporter in hepatocytes

   PMID:29452206

   Open questions at the time

   • Whether SNX10-CTSA interaction occurs on endosomal membranes or in the lumen not established
   • CMA regulation not confirmed in non-hepatic cell types
7. 2019 Medium

   SNX10 was placed upstream of PIKfyve-dependent PI(3,5)P2 synthesis in endosome-to-lysosome maturation, and shown to control autophagosome-lysosome fusion for SRC degradation, establishing SNX10 as a gatekeeper of lysosome biogenesis and macroautophagy flux.

   Evidence Co-IP of SNX10-PIKfyve with epistasis via apilimod; autophagy flux assays and SRC protein levels in SNX10 KO colorectal cells

   PMID:31208298 PMID:31692073

   Open questions at the time

   • Direct biochemical mechanism by which SNX10 activates PIKfyve not determined
   • Whether SRC is a direct autophagy cargo of SNX10-dependent pathway needs confirmation
8. 2021 High

   SNX10 was shown to recruit caspase-5 and PIKfyve to early endosomes for LPS sensing from Gram-negative OMVs, establishing an entirely new innate immune signaling axis linking endosomal sorting to non-canonical inflammasome activation and epithelial barrier integrity.

   Evidence SNX10 KO intestinal epithelial cells and mice; co-IP/recruitment of caspase-5; Lyn phosphorylation and Snail/Slug nuclear translocation; DSS colitis model

   PMID:34747049

   Open questions at the time

   • Whether SNX10 directly binds caspase-5 or acts via a scaffold not resolved
   • Relevance beyond intestinal epithelium not tested
9. 2021 High

   Live imaging of R51Q knock-in osteoclasts revealed that SNX10 limits mature osteoclast fusion by a cell-autonomous membrane homeostasis mechanism; loss of SNX10 causes uncontrolled hyperfusion into giant non-resorptive cells, redefining the osteopetrosis defect as a fusion-arrest failure rather than solely a ruffled-border trafficking defect.

   Evidence R51Q knock-in mice; time-lapse live imaging of osteoclast fusion; lipid-binding and endocytosis assays

   PMID:33975343

   Open questions at the time

   • Molecular mechanism connecting SNX10 lipid binding to fusion arrest not identified
   • Whether hyperfusion alone or combined with trafficking defect causes resorption failure not separated
10. 2024 Medium

    SNX10 was found to stabilize LRP6 (Wnt co-receptor) through direct binding and to control HER2 recycling via RAB11A, broadening SNX10's role to receptor-level regulation of Wnt and RTK signaling with implications for macrophage apoptosis and anti-HER2 drug resistance.

    Evidence CETSA/DARTS for SNX10-LRP6 binding with macrophage-specific KO in vivo; SNX10 KO with RAB11A recycling and HER2 surface expression assays in breast cancer cells

    PMID:39603572 PMID:40228127

    Open questions at the time

    • Whether SNX10-LRP6 interaction is endosome-dependent not shown
    • RAB11A regulation mechanism by SNX10 not defined
11. 2025 High

    SNX10 was identified as a negative regulator of piecemeal mitophagy, linking endosomal vesicles to mitochondrial proteins under stress; its interaction with CLC-7 was shown to control lysosome peripheral distribution in osteoclasts; and SNX10-dependent DEPDC5 degradation was found to activate mTORC1, revealing new roles in mitochondrial quality control, lysosome positioning, and nutrient signaling.

    Evidence SNX10 KO with mitochondrial respiration and citrate synthase assays plus zebrafish; Co-IP of SNX10-CLC-7 with lysosome distribution imaging in osteoclasts; Co-IP of SNX10-DEPDC5 with CMA and mTORC1 assays

    PMID:40052924 PMID:41408708 PMID:41487148

    Open questions at the time

    • Whether SNX10-CLC-7 interaction is the primary mechanism of lysosome positioning or one of several parallel pathways
    • Identity of mitochondrial receptor that links endosomal SNX10 vesicles to mitochondria unknown
    • DEPDC5 degradation mechanism relies on single-lab Co-IP

• Major unresolved questions include the structural basis of SNX10 interactions with its diverse partners (V-ATPase, CLC-7, CTSA, caspase-5, LRP6, DEPDC5), how a single small PXe-domain protein coordinates so many trafficking pathways, and whether its functions in different cell types reflect shared or distinct molecular mechanisms.
• No co-crystal structure of SNX10 with any partner
• No reconstitution of SNX10 sorting activity in minimal systems
• Cell-type-specific interactome not systematically defined