SAXO6

SAXO6/MDM1 is a microtubule-associated protein whose mammalian and yeast lineages reveal a dual role in ciliary microtubule architecture and ER-organelle membrane biology (PMID:26337392, PMID:41742423, PMID:26283797). In mammalian photoreceptors and lung epithelium, SAXO6 co-localizes with ciliary microtubules in both immotile and motile cilia and binds α-tubulin directly, classifying it as a microtubule inner protein (MIP); bi-allelic null variants cause late-onset recessive retinal dystrophy in humans (PMID:41742423). Consistent with a ciliary role, MDM1 localizes to the photoreceptor connecting cilium, where its loss in mice causes opsin mislocalization, intraflagellar transport defects, and progressive outer-segment degeneration (PMID:36171205). In dividing cells, MDM1 resides in the centriole lumen, binds microtubules in vitro through a repeat motif shared with CCSAP, and negatively regulates centriole duplication (PMID:26337392). The yeast ortholog functions in ER membrane biology as an ER-anchored interorganelle tether that contacts the vacuole in trans through its lipid-binding PX domain (PMID:26283797), marks lipid-droplet budding sites and scaffolds fatty-acid activation with the acyl-CoA ligase Faa1 via its PXA domain (PMID:30808705), and mediates TORC1-inactivation-induced nucleolar dynamics and nucleophagy at the nucleus-vacuole junction (PMID:33740659). In colorectal cancer cells, MDM1 overexpression limits YBX1 binding to the TP53 promoter, upregulating p53 and promoting apoptosis (PMID:40200809).

1. 1992 Medium

   Established that MDM1 is required for organelle inheritance, the first functional assignment for the gene.

   Evidence Indirect immunofluorescence and temperature-sensitive mutant analysis in yeast

   PMID:1378448

   Open questions at the time

   • Molecular basis of inheritance defect not defined
   • Cytoplasmic 'spots/arrays' not assigned to a specific organelle or complex
   • Intermediate-filament cross-reactivity not mechanistically explained
2. 2015 High

   Resolved yeast Mdm1 as an ER-anchored tether at ER-vacuole contact sites, defining a membrane contact site function and linking it to SNX14 disease alleles.

   Evidence Fluorescence screen, live-cell imaging, PX-domain truncation/mutagenesis and overexpression hypertethering in yeast

   PMID:26283797

   Open questions at the time

   • In trans vacuolar lipid ligand not identified
   • Relationship between tethering and the earlier organelle-inheritance phenotype unresolved
3. 2015 High

   Identified mammalian MDM1 as a centriole-lumen microtubule-binding protein that restrains centriole duplication, establishing a microtubule-cytoskeletal role distinct from the yeast membrane function.

   Evidence 3D-SIM microscopy, in vitro microtubule-binding assay, repeat-motif mutagenesis, siRNA depletion and overexpression in mammalian cells

   PMID:26337392

   Open questions at the time

   • Mechanism by which MDM1 suppresses duplication not defined
   • Centriolar recruitment partners unknown
4. 2019 High

   Placed yeast Mdm1 in lipid-droplet biogenesis, showing it marks LD bud sites and couples to fatty-acid activation via its PXA domain.

   Evidence Domain mapping, co-enrichment with Faa1, lipid metabolomics, fatty-acid toxicity assay and EM in yeast

   PMID:30808705

   Open questions at the time

   • Direct enzymatic role versus scaffolding not separated
   • Conservation of LD function in mammalian MDM1 not tested
5. 2021 Medium

   Connected Mdm1 to TORC1-dependent nucleolar remodeling and selective nucleophagy at the nucleus-vacuole junction.

   Evidence mdm1Δ deletion, fluorescence microscopy of nucleolar markers, rapamycin-induced TORC1 inactivation in yeast

   PMID:33740659

   Open questions at the time

   • Single primary method
   • Molecular link between NVJ tethering and nucleolar protein migration unresolved
6. 2022 Medium

   Demonstrated MDM1 function at the photoreceptor connecting cilium, tying its loss to IFT defects and retinal degeneration in vivo.

   Evidence Immunofluorescence, Mdm1 knockout mouse, electroretinography, opsin mislocalization and histology

   PMID:36171205

   Open questions at the time

   • Direct molecular role within the cilium not yet defined at this stage
   • Whether opsin mislocalization is a primary IFT defect or secondary not separated
7. 2025 Medium

   Defined a transcriptional axis whereby MDM1 modulates p53 via YBX1, linking it to apoptosis and chemoradiation sensitivity in cancer.

   Evidence Promoter-binding assay, RNA-seq, MDM1 knockout/overexpression and xenografts in colorectal cancer cells

   PMID:40200809

   Open questions at the time

   • Mechanism of how a microtubule/ER protein influences YBX1-promoter occupancy unclear
   • Subcellular site of this activity not localized
8. 2026 High

   Resolved SAXO6 as a microtubule inner protein binding α-tubulin directly within ciliary axonemes and established human disease causation.

   Evidence Ultrastructure expansion microscopy, immuno-gold TEM, cross-linking mass spectrometry, bi-allelic null human variants

   PMID:41742423

   Open questions at the time

   • Structural model of α-tubulin contact not determined
   • Reconciliation of MIP role with yeast membrane functions not addressed

• How the divergent activities — ciliary MIP/microtubule binding versus ER-vacuole tethering and lipid-droplet biogenesis — relate within a single conserved protein remains unresolved.
• No structural model unifying microtubule-binding and lipid/PX-domain functions
• No demonstration of which functions are conserved between yeast and mammalian orthologs
• Mechanism connecting cytoskeletal localization to the p53/YBX1 transcriptional effect unknown