M6PR

M6PR (CD-MPR) is a cargo receptor that cycles between the trans-Golgi network and late endosomes to deliver mannose-6-phosphate-tagged lysosomal enzymes, following an itinerary shared with the larger cation-independent receptor (PMID:1964415). Anterograde TGN-to-endosome sorting is directed by overlapping signals in its cytoplasmic tail: a DXXLL motif (residues 61-65) flanked by acidic residues recruits GGA1 with higher affinity than AP-1, with both interactions independent of CK2-mediated Ser57 phosphorylation (PMID:15044437). Retrograde retrieval from endosomes to the TGN proceeds through the recycling endosome and depends on retromer for early-endosome exit (PMID:22540229), with RUFY1 (recruited via Arl8b/Rab14) coupling cargo to dynein-dynactin (PMID:36282215) and golgin tethers GCC88 and GCC2 completing TGN delivery (PMID:30791178, PMID:31840180); loss of these factors reduces receptor levels, impairs cathepsin-D processing, and lowers lysosomal proteolytic capacity (PMID:30791178). Receptor abundance is further controlled by accelerated proteasomal degradation via the E3 ligase ZNRF2 in senescent cells, impairing lysosomal enzyme trafficking and autolysosomal function (PMID:42065825). Beyond lysosomal biogenesis, M6PR's luminal domain promotes influenza A virus envelope fusion with late-endosomal membranes through interaction with the HA2 ectodomain (PMID:38038885), facilitates endosomal escape of phosphorothioate antisense oligonucleotides (PMID:31840180), and binds STING to sort it into endosomes for degradation, suppressing STING signaling (PMID:40714423).

1. 1990 High

   Establishing where the 46 kDa receptor resides answered whether it shares a trafficking route with the larger M6PR, defining its itinerary between Golgi and late endosomes.

   Evidence Immunofluorescence/immunoperoxidase with anti-cytoplasmic-tail antibodies and base treatment across cell types

   PMID:1964415

   Open questions at the time

   • Did not resolve the molecular machinery directing each transport step
   • Steady-state localization does not establish kinetics of cycling
2. 2004 High

   Mapping the cytoplasmic-tail sorting signals answered how adaptors are recruited for anterograde transport, showing GGA1 and AP-1 bind overlapping acidic/DXXLL signals with distinct affinities and independent of Ser57 phosphorylation.

   Evidence In vitro binding with site-directed mutagenesis plus in vivo co-IP of GGA1/AP-1 with CD-MPR mutants

   PMID:15044437

   Open questions at the time

   • Functional consequence of differential GGA1 vs AP-1 affinity for cargo flux not quantified
   • Role of Ser57 phosphorylation, if any, left unresolved
3. 2012 Medium

   Dissecting retrograde transport answered which compartments and factors are required, placing retromer at early-endosome exit and the recycling endosome as an obligatory waystation.

   Evidence siRNA knockdown of retromer and recycling-endosome ablation with confocal tracking of chimeric CD8-M6PR in HeLa

   PMID:22540229

   Open questions at the time

   • Used a chimeric reporter rather than endogenous receptor
   • Single cell line; EHD1-independence not mechanistically explained
4. 2018 Medium

   Testing the luminal domain answered whether TGN targeting information lies outside the cytoplasmic tail, showing the luminal domain influences correct targeting and links retromer regulation to SNX5.

   Evidence Domain-deletion/chimera mutants with localization imaging and co-IP with retromer/SNX5

   PMID:29988026

   Open questions at the time

   • Mechanism by which the luminal domain dictates sorting unknown
   • Single study, overexpressed constructs
5. 2019 Medium

   Knocking out the golgin GCC88 answered whether trans-Golgi tethering is required for retrieval, linking receptor recycling to lysosomal hydrolase maturation and proteolytic capacity.

   Evidence GCC88 knockout cells with CI-M6PR western/IF, cathepsin-D maturation and lysosomal protease assays

   PMID:30791178

   Open questions at the time

   • Direct GCC88–M6PR contact not demonstrated
   • Single study
6. 2022 High

   Identifying RUFY1 answered how endosome-to-TGN cargo is coupled to a motor, showing Arl8b/Rab14-recruited RUFY1 links the receptor to dynein-dynactin for retrieval and hydrolase delivery.

   Evidence Reciprocal Co-IP, siRNA depletion, dominant-negative and reconstitution with endosomal markers

   PMID:36282215

   Open questions at the time

   • Direct vs indirect RUFY1–M6PR association not fully resolved
   • Studied for CI-M6PR; applicability to CD-M6PR not established
7. 2022 Medium

   Linking RAB31 to receptor trafficking answered a disease-relevant question, showing RAB31 loss downstream of RUNX1 haplodeficiency disrupts M6PR transit at early endosomes in megakaryocytes.

   Evidence siRNA/CRISPR knockdown of RUNX1 and RAB31, patient iPSC-megakaryocytes, RAB31 reconstitution

   PMID:35839075

   Open questions at the time

   • Direct RAB31–M6PR interaction not shown
   • Partial rescue leaves residual mechanism unexplained
8. 2023 High

   Defining CLN3 as an M6PR interactor answered how receptor trafficking integrates with lysosomal reformation, showing CLN3 is required for correct CI-M6PR routing and proto-lysosome formation.

   Evidence Co-IP/proteomics, CLN3 loss- and gain-of-function, enzyme sorting assays and live imaging of lysosomal tubules

   PMID:37400440

   Open questions at the time

   • Whether CLN3 acts on CD-M6PR not addressed
   • Structural basis of the CLN3–M6PR interaction unknown
9. 2023 Medium

   Mapping the M6PR–HA2 interaction answered how the receptor's luminal domain serves viral entry, showing it directly promotes influenza envelope fusion with late-endosomal membranes.

   Evidence siRNA knockdown, Co-IP with HA, domain mapping, step-specific viral entry and NP nuclear accumulation assays

   PMID:38038885

   Open questions at the time

   • Structural detail of the HA2–luminal-domain contact unresolved
   • Generality across virus strains not tested
10. 2025 Medium

    Linking M6PR to STING degradation answered how the receptor can act on innate immune signaling, showing it binds STING and sorts it into endosomes to suppress senescence-associated signaling.

    Evidence Co-IP, endosomal co-localization, cellular thermal shift, M6PR siRNA knockdown rescue in a berberine context

    PMID:40714423

    Open questions at the time

    • Whether STING is an M6P-tagged cargo or bound via another mode unknown
    • Single study; physiological relevance outside drug treatment unclear
11. 2026 Medium

    Identifying ZNRF2-mediated degradation answered how receptor abundance is regulated, defining an mTORC1–ZNRF2–CD-M6PR axis that depletes the receptor and impairs lysosomal function in senescence.

    Evidence Structural prediction with validation, Co-IP, proteasome inhibitor, ZNRF2 knockdown/overexpression and mTORC1 inhibition

    PMID:42065825

    Open questions at the time

    • Ubiquitination site on CD-M6PR not mapped
    • Single study

• How the diverse non-canonical roles (ASO escape, viral fusion, STING sorting) mechanistically relate to the receptor's core lysosomal-enzyme delivery function remains unresolved.
• No unifying structural model for luminal-domain ligand promiscuity
• Whether non-canonical cargoes use the M6P-binding site is unknown