Affinage

MON1A

Vacuolar fusion protein MON1 homolog A · UniProt Q86VX9

Length
652 aa
Mass
72.9 kDa
Annotated
2026-04-28
32 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MON1A is a core subunit of the trimeric MON1-CCZ1-C18orf8 guanine nucleotide exchange factor (GEF) complex that activates RAB7, serving as the master switch for RAB5-to-RAB7 conversion on endosomes, phagosomes, and autophagosomes (PMID:20305638, PMID:33144569). MON1A is recruited to membranes as an effector of GTP-bound RAB5, and the assembled MON1-CCZ1 complex then catalyzes RAB7 GTP loading, which is essential for late-endosomal cholesterol export via NPC1, LDL trafficking, autophagosome–lysosome fusion, and APP-CTF/Aβ degradation (PMID:33144569, PMID:35198070, PMID:37418591). Beyond the endolysosomal system, MON1A functions in anterograde secretory trafficking—including ER-to-Golgi and Golgi-to-plasma-membrane transport of cargoes such as ferroportin—by associating with dynein, and maintains Golgi ribbon integrity through interaction with the F-BAR protein FCHO2 (PMID:17632513, PMID:22665492, PMID:37461455). Loss-of-function variants in MON1A cause congenital diarrhea and enteropathy in humans (PMID:40174224).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 High

    Forward genetics in mice revealed that MON1A is required for trafficking of ferroportin and other secreted/surface molecules, establishing the gene as a fundamental component of the mammalian secretory apparatus.

    Evidence QTL mapping in congenic mouse lines, cell-based ferroportin surface assays, siRNA knockdown

    PMID:17632513

    Open questions at the time
    • Mechanism of MON1A action in secretory trafficking was unknown
    • Whether MON1A functions as part of a complex was not addressed
    • Relationship to endosomal RAB GTPases not yet explored in mammals
  2. 2010 High

    The MON1-CCZ1 complex was identified as a RAB5 effector and RAB7 GEF that drives RAB5-to-RAB7 conversion on phagosomes, establishing the central mechanistic paradigm for MON1A function in membrane maturation.

    Evidence C. elegans sand-1/ccz-1 mutants, mammalian knockdown, co-immunoprecipitation with GTP-RAB5, RAB7 binding and activation assays, phagosome imaging

    PMID:20305638

    Open questions at the time
    • Stoichiometry and structure of the GEF complex were undefined
    • Whether additional subunits exist was unknown
    • Extension to autophagosome maturation was not tested
  3. 2012 High

    MON1A was shown to function in anterograde ER-to-Golgi and Golgi-to-PM trafficking and to associate with dynein, revealing a role distinct from its endosomal RAB7-GEF activity.

    Evidence siRNA knockdown, Endo H assay for ER-to-Golgi traffic, BFA washout, IP-mass spectrometry identifying dynein intermediate chain, immunofluorescence

    PMID:22665492

    Open questions at the time
    • Whether the secretory-trafficking function requires CCZ1 or RAB7 activation was not resolved
    • Direct role of dynein association in MON1A-dependent trafficking was not reconstituted
    • Relationship between Golgi morphology changes and trafficking delays was unclear
  4. 2020 High

    A genome-wide CRISPR screen defined MON1A/B as part of a trimeric MCC (MON1-CCZ1-C18orf8) GEF complex whose RAB7 activation is required for NPC1-dependent lysosomal cholesterol export and LDL trafficking, broadening the physiological scope of MON1A's GEF activity.

    Evidence CRISPR screen and knockout of MON1A/B and C18orf8, RAB7-GTP pull-downs, cholesterol reporters, LDL trafficking assays, constitutively active RAB7 rescue

    PMID:33144569

    Open questions at the time
    • Structural basis for trimeric complex assembly was not determined
    • Tissue-specific contributions of MON1A versus MON1B were unclear
    • Whether C18orf8 has catalytic versus scaffolding roles was not resolved
  5. 2020 Medium

    The MON1A-CCZ1 GEF was placed in the autophagosome maturation pathway through two independent studies: NRBF2 was found to maintain CCZ1-MON1A activity and regulate PI3KC3-dependent RAB7 activation, and FYCO1 was identified as a physical interactor that mediates CCZ1-MON1A-dependent vesicle–lysosome fusion.

    Evidence Co-immunoprecipitation, RAB7-GTP pull-downs, siRNA/KO of NRBF2, APP-CTF degradation assay; AP-MS identifying FYCO1-GOLD domain interaction with MON1A, co-IP validation

    PMID:31992042 PMID:32543313

    Open questions at the time
    • Whether NRBF2 acts directly on the MON1A-CCZ1 complex or via PI3KC3 was not fully separated
    • Structural details of the FYCO1-GOLD domain–MON1A interface were unknown
    • In vivo validation in animal models was lacking
  6. 2022 Medium

    MON1A-CCZ1 GEF activity was shown to be diminished in Alzheimer disease models, with restored overexpression rescuing RAB7 activation, autophagosome maturation, and clearance of Aβ and phospho-tau in vivo, linking the GEF to neurodegeneration-relevant proteostasis.

    Evidence GST-R7BD affinity isolation for GTP-RAB7 in autophagosome fractions, AAV-mediated MON1A expression in mouse brain, immunoblotting

    PMID:35198070

    Open questions at the time
    • Mechanism of GEF activity decline in AD was not identified
    • Whether effects are MON1A-specific or reflect general endolysosomal dysfunction was unclear
    • Independent replication in a second AD model was not reported
  7. 2022 Medium

    The lysosomal V-ATPase a3 subunit was identified as a membrane receptor that recruits MON1A-CCZ1 to secretory lysosomes in osteoclasts, with the interaction mapped to MON1A longin motifs, revealing a mechanism for GEF targeting to specific organelles.

    Evidence Co-immunoprecipitation in HEK293T, longin-motif domain mapping, immunofluorescence in a3-deficient osteoclasts

    PMID:35589873

    Open questions at the time
    • Whether a3-mediated recruitment is required for RAB7 activation in osteoclasts was not directly tested by GEF assay
    • Generality of V-ATPase subunit-dependent GEF recruitment to other cell types was unknown
    • Structural resolution of the longin–a3 interface was lacking
  8. 2023 Medium

    CASP8 cleavage of the FYCO1 GOLD domain was shown to sever the FYCO1–CCZ1-MON1A interaction, blocking RAB7A activation and lysosomal delivery of TRAIL-R2, thereby linking MON1A-dependent vesicle maturation to apoptotic signaling.

    Evidence Two-step co-immunoprecipitation, CRISPR KO of FYCO1, caspase cleavage site mapping, receptor trafficking and apoptosis assays

    PMID:37418591

    Open questions at the time
    • Whether CASP8 cleavage of FYCO1 is the dominant mechanism shutting down MON1A-CCZ1 during apoptosis was not established
    • In vivo relevance of FYCO1-MON1A axis in TRAIL signaling was not tested
  9. 2023 Medium

    MON1A was found to maintain Golgi ribbon architecture through a physical interaction with the F-BAR protein FCHO2, establishing a GEF-independent structural role at the Golgi. (preprint)

    Evidence (preprint) Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, FRAP of Golgi residents

    PMID:37461455

    Open questions at the time
    • Awaits peer review and independent replication
    • Whether this Golgi role requires CCZ1 or RAB7 was not resolved
    • Molecular mechanism by which MON1A-FCHO2 maintains ribbon continuity is unknown
  10. 2025 Medium

    Human loss-of-function variants in MON1A were identified as the cause of congenital diarrhea and enteropathy (CODE), establishing MON1A as a disease gene and demonstrating its essential role in intestinal epithelial function.

    Evidence Exome/genome sequencing of patient cohort, cell model functional assays, zebrafish loss-of-function models

    PMID:40174224

    Open questions at the time
    • Specific intestinal cellular pathway disrupted by MON1A loss (endosomal vs. secretory) was not delineated
    • Whether MON1B compensates in non-intestinal tissues remains unknown
    • Only a single study; independent cohort replication pending

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of trimeric MCC complex assembly and substrate specificity, whether MON1A's secretory/Golgi functions are mechanistically independent of RAB7 GEF activity, and the tissue-specific division of labor between MON1A and MON1B.
  • No high-resolution structure of the human MCC-RAB7 complex exists
  • The GEF-independent versus GEF-dependent functions of MON1A have not been genetically separated
  • Tissue-specific redundancy between MON1A and MON1B is not systematically characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4
Localization
GO:0005764 lysosome 2 GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9612973 Autophagy 3 R-HSA-9609507 Protein localization 2 R-HSA-382551 Transport of small molecules 1
Partners
C18ORF8CCZ1DYNC1I2FCHO2FYCO1NRBF2RAB5RAB7A
Complex memberships
MON1-CCZ1-C18orf8 (MCC) trimeric RAB7 GEF complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 MON1A (and MON1B) are required for phagosome maturation: phagosomes in MON1A-deficient cells recruit RAB5 but fail to progress to the RAB7-positive stage. MON1 interacts with GTP-bound RAB5, identifying MON1 as a RAB5 effector. The MON1-CCZ1 complex (but not either protein alone) binds RAB7 and promotes RAB7 activation, functioning as a critical link in progression from RAB5-positive to RAB7-positive phagosome maturation. Genetic epistasis (C. elegans sand-1/ccz-1 mutants), mammalian cell knockdown, co-immunoprecipitation with GTP-bound RAB5, RAB7 binding assays, phagosome maturation imaging Nature High 20305638
2007 MON1A is required for trafficking of ferroportin (the major mammalian iron exporter) to the macrophage cell surface, and is also important for trafficking of other cell-surface and secreted molecules, indicating a fundamental role in the mammalian secretory apparatus. QTL analysis in mice; missense allele co-segregation; cell-based trafficking assays with surface ferroportin measurement; siRNA knockdown Nature genetics High 17632513
2012 MON1A acts in anterograde secretory trafficking: siRNA knockdown delays ER-to-Golgi traffic (shown by Endo H sensitivity of ts045VSVG-GFP), delays Golgi reformation after Brefeldin A treatment, and delays Golgi-to-plasma membrane trafficking. MON1A associates with dynein intermediate chain (identified by immunoprecipitation and mass spectrometry), and both MON1A and dynein reduction alter steady-state Golgi morphology. siRNA knockdown, Endo H assay, Brefeldin A washout, immunoprecipitation + mass spectrometry, immunofluorescence microscopy The Journal of biological chemistry High 22665492
2020 MON1A/MON1B are components of the trimeric Mon1-Ccz1-C18orf8 (MCC) GEF complex for RAB7. MON1A/B-deficient cells lack RAB7 activation, show severe late endosome morphology defects, impaired endosomal LDL trafficking, and failure of NPC1-dependent lysosomal cholesterol export. Active RAB7 (downstream of MCC GEF activity) interacts with the NPC1 cholesterol transporter to license lysosomal cholesterol export. Genome-wide CRISPR screen, CRISPR knockout of MON1A/B and C18orf8, RAB7 activation assays, cholesterol reporter, late endosome morphology imaging, LDL trafficking assays, constitutively active RAB7 rescue Nature communications High 33144569
2020 NRBF2 maintains CCZ1-MON1A GEF activity by interacting with the CCZ1-MON1A complex, regulating CCZ1-MON1A interaction with PI3KC3/VPS34 and CCZ1-associated PI3KC3 kinase activity; loss of NRBF2 impairs GTP-RAB7 generation and autophagosome maturation. MON1A also participates in the CCZ1-MON1A-RAB7 module that interacts with APP to facilitate degradation of APP-containing vesicles. Co-immunoprecipitation, RAB7-GTP pull-down assay, siRNA/KO of NRBF2, autophagosome maturation assay, APP-CTF degradation assay Autophagy Medium 32543313
2022 MON1A-CCZ1 GEF activity is required for autophagosome maturation in Alzheimer disease models: active RAB7 is selectively decreased in autophagosome fractions from AD models, accompanied by impaired CCZ1-MON1A GEF activity. Overexpressing CCZ1-MON1A increases GTP-RAB7 levels, enhances autophagosome maturation, and promotes degradation of APP-CTFs, Aβ and P-tau in cells and a mouse AD model. GST-R7BD affinity-isolation assay for GTP-RAB7 in autophagosome fractions, AAV-mediated overexpression/knockdown of MON1A in mouse brain, immunoblotting, autophagosome purification, RNA-seq Theranostics Medium 35198070
2022 The lysosomal V-ATPase a3 subunit interacts with MON1A-CCZ1 complex and recruits it to secretory lysosomes in osteoclasts. The interaction is mediated by the N-terminal half domain of a3 and the longin motifs of MON1A and CCZ1. Loss of a3 abolishes lysosomal localization of endogenous CCZ1, and exogenous expression of MON1A-CCZ1 GEF promotes the a3-RAB7 interaction. Co-immunoprecipitation in HEK293T cells, domain mapping (longin motif mutants), immunofluorescence of osteoclasts lacking a3 Scientific reports Medium 35589873
2020 MON1A (via the CCZ1-MON1A complex) interacts with FYCO1 through the FYCO1 C-terminal GOLD domain, as identified by AP-MS and validated by co-immunoprecipitation; this interaction is required for RAB7A activation and fusion of autophagosomal/endosomal vesicles with lysosomes. Affinity purification-mass spectrometry (AP-MS) with spin-tip IMAC columns, co-immunoprecipitation validation Analytical chemistry Medium 31992042
2023 FYCO1 interacts via its C-terminal GOLD domain with the CCZ1-MON1A complex; this interaction is necessary for RAB7A activation and lysosomal delivery of TNFRSF10B/TRAIL-R2. CASP8 cleaves FYCO1 at aspartate 1306, releasing the GOLD domain and inactivating FYCO1 function, thereby preventing further CCZ1-MON1A-dependent vesicle-lysosome fusion and allowing apoptosis to proceed. Co-immunoprecipitation (two-step), CRISPR KO of FYCO1, apoptosis assays, receptor trafficking/lysosomal degradation assays, caspase cleavage site identification Autophagy Medium 37418591
2024 GORASP2 controls RAB7A activity by modulating its GEF complex MON1A-CCZ1, and this is required for RAB7A interaction with the HOPS complex and autophagosome-lysosome fusion during glucose starvation. Super-resolution microscopy, siRNA depletion of GORASP2, RAB7A activation assay, co-immunoprecipitation, SNARE complex assembly assay Autophagy Medium 39056394
2023 MON1A is required for maintenance of Golgi ribbon architecture. MON1A interacts with the F-BAR protein FCHO2 (identified by yeast two-hybrid and co-immunoprecipitation). siRNA depletion of MON1A or FCHO2 causes Golgi fragmentation and prevents exchange of resident membrane proteins between Golgi ministacks (shown by FRAP). MON1A-silencing effect on Golgi disruption is cell cycle-independent, whereas FCHO2-silencing effect requires mitosis. Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, immunofluorescence, FRAP analysis bioRxivpreprint Medium 37461455
2025 MON1A variants cause congenital diarrhea and enteropathy (CODE) in humans. Functional characterization in cell and zebrafish models demonstrated that MON1A loss-of-function results in intestinal disease, establishing MON1A as a novel CODE gene. Exome/genome sequencing of patient cohort, cell model functional assays, zebrafish loss-of-function models The New England journal of medicine Medium 40174224

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Identification of two evolutionarily conserved genes regulating processing of engulfed apoptotic cells. Nature 202 20305638
2010 Rab7: role of its protein interaction cascades in endo-lysosomal traffic. Cellular signalling 181 20851765
2007 Caenorhabditis elegans SAND-1 is essential for RAB-7 function in endosomal traffic. The EMBO journal 92 17203072
2020 A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export. Nature communications 75 33144569
2007 Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice. Nature genetics 60 17632513
2018 Mycobacterial PknG Targets the Rab7l1 Signaling Pathway To Inhibit Phagosome-Lysosome Fusion. Journal of immunology (Baltimore, Md. : 1950) 59 30037848
2013 Dmon1 controls recruitment of Rab7 to maturing endosomes in Drosophila. Journal of cell science 44 23418349
2020 NRBF2 is a RAB7 effector required for autophagosome maturation and mediates the association of APP-CTFs with active form of RAB7 for degradation. Autophagy 43 32543313
2016 Selection and Validation of Reference Genes for Quantitative Real-time PCR in Gentiana macrophylla. Frontiers in plant science 34 27446172
2018 Function and regulation of the Caenorhabditis elegans Rab32 family member GLO-1 in lysosome-related organelle biogenesis. PLoS genetics 32 30419011
2022 Enhancing autophagy maturation with CCZ1-MON1A complex alleviates neuropathology and memory defects in Alzheimer disease models. Theranostics 26 35198070
2014 Identification of suitable qPCR reference genes in leaves of Brassica oleracea under abiotic stresses. Ecotoxicology (London, England) 23 24566730
2014 Caenorhabditis elegans HOPS and CCZ-1 mediate trafficking to lysosome-related organelles independently of RAB-7 and SAND-1. Molecular biology of the cell 22 24501423
2020 Probing Protein-Protein Interactions with Label-Free Mass Spectrometry Quantification in Combination with Affinity Purification by Spin-Tip Affinity Columns. Analytical chemistry 21 31992042
2014 Loss of the Sec1/Munc18-family proteins VPS-33.2 and VPS-33.1 bypasses a block in endosome maturation in Caenorhabditis elegans. Molecular biology of the cell 18 25273556
2005 A role of SAND-family proteins in endocytosis. Biochemical Society transactions 17 16042554
2023 The autophagic protein FYCO1 controls TNFRSF10/TRAIL receptor induced apoptosis and is inactivated by CASP8 (caspase 8). Autophagy 15 37418591
2022 The lysosomal V-ATPase a3 subunit is involved in localization of Mon1-Ccz1, the GEF for Rab7, to secretory lysosomes in osteoclasts. Scientific reports 15 35589873
2021 Sphingomonas sabuli sp. nov., a carotenoid-producing bacterium isolated from beach sand. International journal of systematic and evolutionary microbiology 15 34323678
2020 Identification and evaluation of reliable reference genes for quantitative real-time PCR analysis in tea plants under differential biotic stresses. Scientific reports 14 32051495
2020 Hexa-Longin domain scaffolds for inter-Rab signalling. Bioinformatics (Oxford, England) 13 31562761
2025 Coordination between ESCRT function and Rab conversion during endosome maturation. The EMBO journal 12 39910226
2016 A fresh look at the function of Rabaptin5 on endosomes. Small GTPases 8 26940354
2012 Mon1a protein acts in trafficking through the secretory apparatus. The Journal of biological chemistry 8 22665492
2021 Extending the Horizon of Homology Detection with Coevolution-based Structure Prediction. Journal of molecular biology 7 34139218
2025 The Genetic Architecture of Congenital Diarrhea and Enteropathy. The New England journal of medicine 6 40174224
2024 GORASP2 promotes phagophore closure and autophagosome maturation into autolysosomes. Autophagy 6 39056394
2009 Forward genetics used to identify new gene Mon1a with critical role in controlling macrophage iron metabolism and iron recycling from erythrocytes. Nutrition reviews 5 19785692
2025 Genetic architecture of the murine red blood cell proteome reveals central role of hemoglobin beta cysteine 93 in maintaining redox balance. Cell genomics 2 41265446
2025 Genetic architecture of the red blood cell proteome in genetically diverse mice reveals central role of hemoglobin beta cysteine redox status in maintaining circulating glutathione pools. bioRxiv : the preprint server for biology 0 40093052
2023 Mon1a and FCHO2 are required for maintenance of Golgi architecture. bioRxiv : the preprint server for biology 0 37461455
2013 Epistasis in iron metabolism: complex interactions between Cp, Mon1a, and Slc40a1 loci and tissue iron in mice. Mammalian genome : official journal of the International Mammalian Genome Society 0 24121729