Affinage

MON2

Protein MON2 homolog · UniProt Q7Z3U7

Length
1717 aa
Mass
190.4 kDa
Annotated
2026-04-28
13 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MON2 is a large scaffold protein that operates at the trans-Golgi network and endosomes to coordinate retrograde membrane trafficking, recycling-endosome biogenesis, and autophagy. MON2 nucleates a conserved complex with DOPEY1/DOPEY2 and the aminophospholipid translocase ATP9A on endosomal membranes; this complex associates with SNX3-retromer to mediate endosome-to-Golgi retrieval of cargo such as Wntless, thereby regulating Wnt secretion, and drives the physical separation of recycling endosomes from early endosomes required for transferrin receptor recycling (PMID:30213940, PMID:32404555). MON2 senses phosphatidic acid for its Golgi targeting and, together with DOPEY1 (which binds PI4P), recruits kinesin-1 and dynein/dynactin motors to enable bidirectional organelle transport; it also couples endocytosis to actin remodeling through interactions with the nucleators Cappuccino and Spire (PMID:31324769, PMID:21610029). Under nutrient stress, MON2 translocates from the Golgi to endosomes, binds and activates GABARAPL2/LGG-1, and promotes autophagic flux (PMID:34860542).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2005 High

    Establishing that Mon2 is a trans-Golgi scaffold that recruits Dop1 and is required for endosome-to-Golgi cycling resolved Mon2's core cellular role as a trafficking organizer rather than a catalytic GEF.

    Evidence Yeast deletion mutants, fluorescence localization, and co-immunoprecipitation of Mon2–Dop1

    PMID:16301316

    Open questions at the time
    • Mammalian conservation of the Mon2–Dop1 interaction not yet tested
    • Mechanism by which Mon2 recruits Dop1 to the Golgi unknown
    • No identification of specific cargo sorted by Mon2
  2. 2011 High

    Demonstration that Drosophila Mon2 couples Oskar-triggered endocytosis to actin remodeling via Cappuccino and Spire established that Mon2 scaffolding extends beyond vesicle trafficking to cytoskeletal regulation.

    Evidence Reciprocal co-immunoprecipitation, genetic epistasis, and live imaging in Drosophila oocytes

    PMID:21610029

    Open questions at the time
    • Whether MON2–actin nucleator interaction is conserved in mammals is untested
    • Structural basis of MON2 interaction with Cappuccino/Spire undefined
  3. 2012 Medium

    Genetic evidence that Mon2 negatively regulates the GTPase Arl1 placed Mon2 upstream of a major Golgi-localized GTPase signaling axis.

    Evidence Synthetic lethality and nucleotide-binding allele epistasis in yeast

    PMID:22594927

    Open questions at the time
    • No biochemical demonstration of direct Mon2-Arl1 interaction
    • Whether MON2 acts on Arl1 in mammalian cells is unknown
    • Single laboratory study
  4. 2018 High

    Identification of the conserved MON2–DOPEY2–ATP9A complex and its association with SNX3-retromer for Wntless retrieval defined the molecular machinery through which MON2 controls endosome-to-Golgi retrograde sorting and Wnt signaling.

    Evidence Reciprocal co-immunoprecipitation in human cells, C. elegans RNAi phenocopy of SNX3-retromer loss, ATPase-dead mutant rescue

    PMID:30213940

    Open questions at the time
    • How the flippase activity of ATP9A is coordinated with SNX3-retromer tubule formation is unclear
    • Direct structural interface between MON2 and SNX3-retromer not mapped
  5. 2019 High

    Showing that MON2 binds phosphatidic acid and partners with PI4P-sensing DOPEY1 to recruit kinesin-1 revealed a dual-lipid-regulated cargo adaptor mechanism coupling membrane identity to motor-driven transport.

    Evidence Lipid-binding assays, co-immunoprecipitation, domain mapping, kinesin-1 pulldown

    PMID:31324769

    Open questions at the time
    • Whether MON2's PA-binding domain is required in vivo for Golgi localization not tested by mutation
    • Relative contributions of kinesin-1 vs dynein/dynactin to MON2-dependent transport unresolved
  6. 2020 High

    Demonstrating that MON2 knockout abolishes recycling-endosome biogenesis and impairs both transferrin receptor recycling and Wntless retrograde transport established MON2 as an essential determinant of RE–EE segregation.

    Evidence MON2/DOPEY2 knockout cells, live imaging, transferrin recycling and Wntless transport assays

    PMID:32404555

    Open questions at the time
    • Molecular mechanism by which MON2 initiates RE tubule formation is undefined
    • Whether MON2 directly remodels membrane or acts through effectors is unknown
  7. 2021 Medium

    Discovery that MON2 translocates from Golgi to endosomes under starvation and activates GABARAPL2/LGG-1 to promote autophagy expanded MON2's role from constitutive trafficking to stress-responsive autophagy regulation.

    Evidence Co-immunoprecipitation of MON2–GABARAPL2, autophagic flux assays in mammalian cells, C. elegans genetic knockdown

    PMID:34860542

    Open questions at the time
    • Single laboratory study; independent confirmation needed
    • Signal triggering MON2 Golgi-to-endosome translocation under starvation is unidentified
    • Whether MON2-dependent autophagy is mechanistically linked to its recycling-endosome function is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MON2 coordinates its dual roles in recycling-endosome biogenesis and autophagy, and whether its membrane-remodeling function is intrinsic or mediated entirely through ATP9A flippase activity and motor recruitment, remain major open questions.
  • No high-resolution structure of MON2 or the MON2–DOPEY2–ATP9A complex
  • Physiological cargo repertoire beyond Wntless and transferrin receptor largely uncharacterized
  • In vivo roles of MON2 in mammalian development or disease not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4
Localization
GO:0005768 endosome 3 GO:0005794 Golgi apparatus 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 1 R-HSA-9612973 Autophagy 1
Partners
ARL1ATP9ADOPEY1DOPEY2GABARAPL2KIF5B
Complex memberships
MON2–DOPEY1–kinesin-1MON2–DOPEY2–ATP9A

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Yeast Mon2 localizes to the trans-Golgi and forms a complex with Dop1 (human DOPEY orthologue); deletion of Mon2 causes mislocalization of Dop1 from the Golgi, demonstrating that Mon2 acts as a scaffold to recruit the Golgi-localized pool of Dop1. Loss of Mon2 also causes defects in endosome-to-Golgi cycling. Yeast genetics, subcellular localization (fluorescence microscopy), co-immunoprecipitation, deletion mutant analysis The Journal of biological chemistry High 16301316
2011 Drosophila Mon2 (ortholog) acts downstream of Oskar at the oocyte posterior to remodel cortical actin and anchor germ plasm. Mon2 physically interacts with actin nucleators Cappuccino and Spire, promotes Rho1 accumulation at the posterior, and couples Oskar-induced endocytosis with F-actin projection formation, functioning as a scaffold on vesicles. Genetic epistasis (Drosophila loss-of-function), co-immunoprecipitation (Mon2 with Capu/Spire), live imaging, subcellular localization Development (Cambridge, England) High 21610029
2011 Human MON2 (hMon2) is required for efficient production of infectious HIV-1 virions; depletion of hMon2 in human cells reduces infectious particle production, consistent with its role in protein trafficking to the plasma membrane. siRNA knockdown in human cells, HIV-1 Gag VLP release assay, yeast genetic screen Journal of virology Medium 21450827
2012 In yeast, MON2 functions as a negative regulator of the GTP-restricted form of the monomeric G protein Arl1, as demonstrated by synthetic lethality and nucleotide-binding allele epistasis experiments. Yeast genetic epistasis, site-directed mutagenesis of ARL1, synthetic lethality analysis FEMS yeast research Medium 22594927
2018 Human MON2 forms an evolutionarily conserved endosome-associated complex with DOPEY2 and the putative aminophospholipid translocase ATP9A; this complex associates with SNX3-retromer to mediate endosome-to-Golgi transport of Wntless. Phospholipid flippase activity of ATP9A contributes to SNX3-retromer-mediated Wntless sorting and Wnt secretion. In vivo suppression of Ce-mon-2, Ce-pad-1 (DOPEY2 orthologue), or Ce-tat-5 (ATP9A orthologue) phenocopies loss of SNX3-retromer function. Co-immunoprecipitation, in vivo C. elegans RNAi knockdown, ATPase-inhibited mutant (TAT-5 E246Q) overexpression, lysosomal degradation assay, Wnt signaling readout Nature communications High 30213940
2019 Dopey1 and Mon2 assemble into a complex that localizes to the Golgi, endolysosome, and ER exit sites. Golgi localization of Mon2 requires binding to phosphatidic acid, while Dopey1 requires phosphatidylinositol-4-phosphate. The N-terminus of Dopey1 interacts with kinesin-1, making the Dopey1-Mon2 complex a dual-lipid-regulated cargo adaptor that recruits kinesin-1 for centrifugally biased bidirectional membrane transport. Co-immunoprecipitation, lipid-binding assays, subcellular localization (fluorescence microscopy), kinesin-1 pulldown, domain mapping Nature communications High 31324769
2020 MON2 drives separation of recycling endosomes (RE) from early endosomes (EE) and is required for formation of a tubular RE network. MON2 co-localizes with RE marker RAB4B; MON2 knockout impairs segregation of RE from EE and intracellular transferrin receptor recycling. DOPEY2 membrane recruitment depends on MON2 expression, and DOPEY2 binds kinesin and dynein/dynactin motors. MON2 is required for retrograde transport of Wntless through RE before delivery to the Golgi. MON2/DOPEY2 knockout cells, live imaging, subcellular co-localization, transferrin receptor recycling assay, Wntless transport assay Cell structure and function High 32404555
2021 Mammalian MON2 physically interacts with GABARAPL2 (mammalian Atg8 orthologue) and this interaction increases autophagic flux in mammalian cells; C. elegans MON-2 similarly activates the GABARAP orthologue LGG-1. Under starvation, MON2 translocates from the Golgi to the endosome and upregulates autophagy. Co-immunoprecipitation (MON2–GABARAPL2), autophagic flux assays in mammalian cells, C. elegans genetic knockdown, subcellular localization under starvation Science advances Medium 34860542

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion. Nature communications 69 30213940
2011 Drosophila Mon2 couples Oskar-induced endocytosis with actin remodeling for cortical anchorage of the germ plasm. Development (Cambridge, England) 34 21610029
2005 Mon2, a relative of large Arf exchange factors, recruits Dop1 to the Golgi apparatus. The Journal of biological chemistry 34 16301316
2019 Dopey1-Mon2 complex binds to dual-lipids and recruits kinesin-1 for membrane trafficking. Nature communications 28 31324769
2011 The cellular factors Vps18 and Mon2 are required for efficient production of infectious HIV-1 particles. Journal of virology 17 21450827
2021 MON-2, a Golgi protein, mediates autophagy-dependent longevity in Caenorhabditis elegans. Science advances 16 34860542
2020 MON2 Guides Wntless Transport to the Golgi through Recycling Endosomes. Cell structure and function 13 32404555
2020 Mon2-monocytes and increased CD-11b expression before transcatheter aortic valve implantation are associated with earlier death. International journal of cardiology 12 32413468
2012 Mon2 is a negative regulator of the monomeric G protein, Arl1. FEMS yeast research 5 22594927
2022 MON-2, a Golgi protein, promotes longevity by upregulating autophagy through mediating inter-organelle communications. Autophagy 4 35188063
2020 MicroRNA-133a-5p inhibiting metastatic capacity of renal clear cell carcinoma through regulating MON2. European review for medical and pharmacological sciences 4 32572912
2024 Targeted RNA sequencing in diagnostically challenging head and neck carcinomas identifies novel MON2::STAT6, NFATC2::NUTM2B, POC5::RAF1, and NSD3::NCOA2 gene fusions. Histopathology 3 39628352
2021 Novel MLL/KMT2A-MON2 fusion in a child with therapy-related acute myeloid leukemia after treatment for acute promyelocytic leukemia. Molecular carcinogenesis 3 34236108