Affinage

CHML

Rab proteins geranylgeranyltransferase component A 2 · UniProt P26374

Length
656 aa
Mass
74.1 kDa
Annotated
2026-06-09
10 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHML encodes REP-2, a Rab escort protein that binds newly synthesized Rab GTPases and presents them to the catalytic component of Rab geranylgeranyltransferase for attachment of geranylgeranyl groups, with substrate selectivity dictated by the Rab C-terminus (PMID:8294464). In vitro reconstitution showed REP-2 supports prenylation of Rab1A, Rab5A, and Rab6 comparably to REP-1 but is markedly less active toward Rab3A and Rab3D, and swapping the C-terminal 12 residues of Rab3A for those of Rab1A restores full REP-2 activity, establishing the Rab C-terminus as the specificity determinant (PMID:8294464). In cancer contexts, CHML escorts Rab14 to the membrane to sustain its recycling, with Rab14-positive vesicles carrying the metastasis regulators Mucin13 and CD44 as cargoes to drive hepatocellular carcinoma migration, invasion, and metastasis (PMID:31175290). CHML is a transcriptional target of NRF2 through an antioxidant response element in its promoter and is required for mTOR translocation and activation at the lysosome (PMID:35184380).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1994 High

    Established the biochemical function of the CHML product REP-2 as a Rab escort protein and resolved how it discriminates among Rab substrates, defining the molecular basis of its prenylation role.

    Evidence In vitro geranylgeranylation assay with recombinant REP-1/REP-2 and C-terminal Rab3A/Rab1A chimeric mutagenesis

    PMID:8294464

    Open questions at the time
    • Does not address physiological consequences of REP-2 versus REP-1 specificity in cells
    • No structural model of the REP-2/Rab/transferase complex
    • Cellular pathways downstream of REP-2-mediated prenylation not examined
  2. 2019 Medium

    Connected REP-2 escort activity to a disease phenotype by showing CHML drives metastasis through Rab14 membrane recycling and delivery of specific vesicle cargoes.

    Evidence siRNA knockdown/overexpression in HCC lines, Rab14 rescue, membrane fractionation, cargo identification, and in vivo metastasis models

    PMID:31175290

    Open questions at the time
    • Direct prenylation of Rab14 by CHML not biochemically reconstituted here
    • Mechanism linking Rab14 vesicles to Mucin13/CD44 loading not detailed
    • Generality beyond HCC unknown
  3. 2021 Low

    Extended CHML's proliferative role to NSCLC and reported a direct physical interaction with Rab5A consistent with its escort function.

    Evidence Co-immunoprecipitation, siRNA knockdown, xenograft model, and miR-199a-3p modulation with CHML rescue

    PMID:34649053

    Open questions at the time
    • Binding rests on a single Co-IP without reciprocal validation
    • No demonstration that Rab5A prenylation mediates the proliferative effect
    • Functional dependence on Rab5A not tested by rescue
  4. 2022 Medium

    Placed CHML within a redox-responsive transcriptional circuit and tied it to nutrient signaling by showing it is an NRF2 target required for lysosomal mTOR activation.

    Evidence ARE promoter analysis plus knockdown/overexpression in A549 cells with mTOR lysosomal localization and proliferation assays

    PMID:35184380

    Open questions at the time
    • Mechanistic link between Rab escort activity and mTOR recruitment unresolved
    • Direct NRF2 occupancy at the ARE not confirmed by ChIP
    • Identity of the relevant Rab(s) at the lysosome not established
  5. 2025 Low

    Proposed a metabolic axis whereby CHML promotes invasion via SLC44A3-driven choline uptake and phosphatidic acid production feeding MAPK and PI3K-AKT signaling.

    Evidence CHML knockout/overexpression with transcriptomics, untargeted metabolomics, integrated multi-omics, migration/invasion assays, and xenografts

    PMID:40842592

    Open questions at the time
    • SLC44A3-PA-MAPK/PI3K axis inferred from omics with limited direct validation
    • How CHML escort activity upregulates SLC44A3 is unknown
    • Causal contribution of PA to signaling not demonstrated by perturbation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CHML/REP-2's core prenylation-escort biochemistry mechanistically connects to its diverse cancer phenotypes (mTOR activation, choline metabolism, cargo-specific vesicle trafficking) remains unresolved.
  • No structural model of REP-2 substrate engagement in a cellular context
  • Causal chain from Rab prenylation to specific signaling outputs not reconstituted
  • Tissue-specific REP-2 versus REP-1 functional division not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1 GO:0140096 catalytic activity, acting on a protein 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 1
Partners
RAB14RAB1ARAB5ARAB6

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 REP-2 (encoded by CHML) functions as a Rab escort protein that binds newly synthesized Rab proteins and facilitates attachment of geranylgeranyl (GG) groups by the catalytic component of Rab GG transferase. REP-2 was approximately equal to REP-1 in supporting GG transfer to Rab1A, Rab5A, and Rab6, but only 25% as active as REP-1 toward Rab3A and Rab3D. Replacing the C-terminal 12 amino acids of Rab3A with those of Rab1A restored REP-2 activity to REP-1 levels, demonstrating that substrate specificity is determined by the Rab C-terminus. In vitro geranylgeranylation assay using recombinantly produced REP-1 and REP-2; C-terminal chimeric Rab3A/Rab1A mutagenesis The Journal of biological chemistry High 8294464
2019 CHML promotes HCC cell migration, invasion, and metastasis in a Rab14-dependent manner by escorting Rab14 to the membrane to facilitate its constant recycling. Rab14-positive vesicles carry metastasis regulators Mucin13 and CD44 as cargoes, contributing to the pro-metastatic effect. siRNA knockdown and overexpression of CHML in HCC cell lines; rescue experiments with Rab14; membrane fractionation; identification of Rab14-vesicle cargoes; in vivo metastasis models Nature communications Medium 31175290
2021 CHML promotes NSCLC cell proliferation by directly binding to Rab5A, as demonstrated by co-immunoprecipitation assay. Co-immunoprecipitation; siRNA knockdown; xenograft mouse model; miR-199a-3p overexpression/inhibition with CHML rescue Pathology, research and practice Low 34649053
2022 CHML (Rep2) is a transcriptional target of NRF2 via an antioxidant response element (ARE) in its promoter (-1622 to -1612). Mechanistically, Rep2 mediates mTOR function: loss of Rep2 inhibited mTOR translocation and activation at the lysosome, while overexpression enhanced it. ARE-promoter analysis; siRNA knockdown and overexpression in A549 NSCLC cells; mTOR lysosomal localization assay; proliferation assay Molecular oncology Medium 35184380
2025 CHML promotes HCC cell migration and invasion by upregulating SLC44A3 to enhance choline uptake, thereby increasing phosphatidic acid (PA) production, which activates MAPK and PI3K-AKT signaling cascades. CHML knockout and overexpression; transcriptome sequencing; untargeted metabolomics; integrated multi-omics pathway analysis; wound healing and Transwell assays; xenograft models Frontiers in oncology Low 40842592

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 REP-2, a Rab escort protein encoded by the choroideremia-like gene. The Journal of biological chemistry 159 8294464
2019 CHML promotes liver cancer metastasis by facilitating Rab14 recycle. Nature communications 43 31175290
2003 Identification, cDNA cloning and possible roles of seed-specific rice asparaginyl endopeptidase, REP-2. Planta 20 12684786
1994 Mapping of the choroideremia-like (CHML) gene at 1q42-qter and mutation analysis in patients with Usher syndrome type II. Genomics 15 8188272
2023 Bioengineered Hybrid Rep 2/6 Gene Improves Encapsulation of a Single-Stranded Expression Cassette into AAV6 Vectors. Genes 5 37895215
2022 CHML is an NRF2 target gene that regulates mTOR function. Molecular oncology 5 35184380
2021 CHML targeted by miR-199a-3p promotes non-small cell lung cancer cell growth via binding to Rab5A. Pathology, research and practice 5 34649053
2001 Antitumor activity of cytotropic heterogeneous molecular lipids (CHML) on human breast cancer xenograft in nude mice. Anticancer research 4 11724310
1999 CHML suppresses cell growth and induces apoptosis in multiple human tumor lines. Anticancer research 3 10652570
2025 CHML regulates migration and invasion in hepatocellular carcinoma via transcriptional and metabolic reprogramming. Frontiers in oncology 0 40842592

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