Affinage

CHMP1A

Charged multivesicular body protein 1a · UniProt Q9HD42

Length
196 aa
Mass
21.7 kDa
Annotated
2026-06-09
20 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHMP1A is an ESCRT-III-class protein that operates at the boundary of two compartments — multivesicular bodies in the cytoplasm and the nuclear matrix — coupling endosomal membrane sorting to chromatin-dependent control of progenitor proliferation (PMID:11559748, PMID:11559747, PMID:23023333). At early/late endosomes it physically associates with the AAA-ATPase SKD1/VPS4 and is required for multivesicular body sorting, where its loss disrupts endosomal architecture and cargo delivery, and its yeast and Drosophila orthologs behave as class E vacuolar sorting factors that downregulate receptors through the MVB pathway (PMID:11559748, PMID:24753138). CHMP1A drives intraluminal vesicle formation and is required for secretion of Sonic Hedgehog on a distinct AXL/RAB18/TMED10-positive extracellular vesicle subtype; in its absence both ILV formation and SHH secretion fail, reducing cortical and cerebellar progenitor proliferation (PMID:30044992). In a parallel nuclear role, CHMP1A localizes to the nuclear matrix, recruits the Polycomb protein BMI1 to condensed chromatin, and is required for BMI1-mediated repression of the INK4A locus; biallelic loss-of-function mutations in CHMP1A cause pontocerebellar hypoplasia, and mutant cells show derepressed INK4A and impaired proliferation, a defect placed upstream of BMI1/INK4A by zebrafish epistasis (PMID:11559747, PMID:23023333). CHMP1A also restrains cell growth via a p53 axis: nuclear, NLS-dependent CHMP1A activates ATM kinase to phosphorylate p53, and acts as a tumor suppressor whose loss promotes anchorage-independent growth (PMID:18787405, PMID:21705858). CHMP1A is phosphorylated at Ser179/Ser182 in its C-terminus, modification dispensable for binding the ESCRT partner IST1 (PMID:23748770).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2001 High

    Established CHMP1 as an endosomal ESCRT-type sorting factor by linking it physically and genetically to the MVB machinery, defining its core membrane-trafficking identity.

    Evidence Co-immunoprecipitation with SKD1/VPS4, fractionation/ICC localization, and yeast CHM1 deletion with carboxypeptidase sorting assays

    PMID:11559748

    Open questions at the time
    • Does not define the order of CHMP1A action within ESCRT-III assembly
    • No structural basis for the VPS4/SKD1 interaction
  2. 2001 Medium

    Revealed an unexpected nuclear function by showing CHMP1 partitions to the nuclear matrix and recruits BMI1 to condensed chromatin, raising the question of how an endosomal protein contributes to gene silencing.

    Evidence Fractionation, ICC, BMI1 recruitment co-localization, and Xenopus PcG functional assay

    PMID:11559747

    Open questions at the time
    • Mechanism of CHMP1A nuclear import not defined here
    • Direct chromatin or BMI1 binding interface not resolved
    • Relationship between endosomal and nuclear pools unclear
  3. 2008 Medium

    Connected CHMP1A to growth suppression by demonstrating it behaves as a tumor suppressor acting through p53, extending its role beyond trafficking into proliferation control.

    Evidence shRNA silencing and overexpression in PanC-1 cells, soft agar and xenograft assays, Western blot for p53/phospho-p53

    PMID:18787405

    Open questions at the time
    • Did not identify how CHMP1A elevates p53
    • Correlative phospho-p53 readout without upstream kinase identification
  4. 2011 Medium

    Identified the molecular route from CHMP1A to p53 by showing nuclear, NLS-dependent CHMP1A activates ATM kinase, mechanistically linking its nuclear localization to growth suppression.

    Evidence NLS-deletion mutants, in vitro ATM kinase assay, p53 reporter, IF co-localization, and ATM-inhibitor epistasis

    PMID:21705858

    Open questions at the time
    • How CHMP1A activates ATM mechanistically is unresolved
    • Whether ATM activation is direct or via DNA damage signaling not established
  5. 2012 High

    Provided causal disease and mechanistic anchoring by showing CHMP1A loss-of-function causes pontocerebellar hypoplasia and acts upstream of BMI1-mediated INK4A repression in CNS progenitors.

    Evidence Human LOF genetics, ChIP for BMI1/INK4A, and zebrafish morpholino knockdown with INK4A-ortholog rescue

    PMID:23023333

    Open questions at the time
    • How CHMP1A controls BMI1 chromatin recruitment in vivo not detailed
    • Connection between trafficking defects and chromatin phenotype not unified
  6. 2013 Medium

    Mapped post-translational regulation by identifying C-terminal phosphorylation sites and testing their role in partner binding, refining the protein's regulatory features.

    Evidence Site-directed mutagenesis, phosphate-affinity PAGE, and Co-IP with IST1

    PMID:23748770

    Open questions at the time
    • Kinase responsible for Ser179/Ser182 phosphorylation unknown
    • Functional consequence of phosphorylation beyond IST1 binding untested
  7. 2018 High

    Unified the trafficking and developmental roles by showing CHMP1A drives ILV formation required for SHH secretion on a defined ART-EV subtype, explaining the progenitor proliferation defect.

    Evidence Chmp1a null mouse, electron microscopy, EV proteomics, cerebral organoid knockdown, and SHH secretion assay

    PMID:30044992

    Open questions at the time
    • How ART-EV subtype specificity is determined not resolved
    • Relationship between SHH-EV secretion and the nuclear INK4A pathway not reconciled
  8. 2021 Medium

    Extended CHMP1A function into iron handling and cell death by placing it with DPEP1 in a ferroptosis pathway causally linked to kidney disease.

    Evidence Mouse KO models, single-cell chromatin accessibility, fine-mapping genome editing, and cellular ferroptosis assays

    PMID:34426578

    Open questions at the time
    • Molecular mechanism linking CHMP1A to iron trafficking not defined
    • Whether ferroptosis role connects to ESCRT activity unknown
  9. 2022 Low

    Proposed an mTOR-coupled apoptotic axis in renal carcinoma, positioning p53 elevation downstream of PI3K/mTOR inhibition by CHMP1A.

    Evidence Overexpression in A498/786-0 cells, Western blot, shRNA-p53 epistasis, colony/MTT and apoptosis assays

    PMID:35583792

    Open questions at the time
    • Single-lab overexpression study with single-method readouts per node
    • How CHMP1A inhibits PI3K/mTOR not established
  10. 2022 Low

    Implicated the Chmp1 ortholog in tissue lipid storage by linking fat-body cell number and size to triglyceride accumulation, hinting at a broader role in organ growth.

    Evidence Drosophila fat-body tissue-specific RNAi and overexpression with triglyceride and cell-size measurements

    PMID:36649042

    Open questions at the time
    • No molecular mechanism identified
    • Relevance to mammalian CHMP1A untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CHMP1A's cytoplasmic ESCRT-III/ILV function and its nuclear matrix/BMI1/ATM functions are mechanistically coordinated within one protein remains unresolved.
  • No structural or interaction model unifying endosomal and nuclear pools
  • Signals partitioning CHMP1A between compartments unknown
  • Whether trafficking and chromatin defects share a common molecular cause undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005768 endosome 2 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1266738 Developmental Biology 2 R-HSA-4839726 Chromatin organization 2
Partners
ATMBMI1IST1VPS4
Complex memberships
ESCRT-III

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 CHMP1 localizes to early endosomes and physically interacts with SKD1/VPS4, a protein directly linked to multivesicular body (MVB) sorting; overexpression of a CHMP1 fusion protein dilates endosomal compartments and disrupts endosomal marker distribution. Deletion of the yeast homolog CHM1 causes defective sorting of carboxypeptidases S and Y and produces abnormal multi-lamellar prevacuolar compartments, classifying it as a class E vacuolar protein sorting gene. Immunocytochemistry, biochemical fractionation, co-immunoprecipitation/physical interaction assay, yeast deletion genetics with sorting assays Journal of cell science High 11559748
2001 CHMP1 distributes to both cytoplasm and nuclear matrix; overexpressed CHMP1 localizes to punctate subnuclear structures encapsulating condensed chromatin, recruits PcG protein BMI1 to these regions, and cooperates with vertebrate Pcl in a Xenopus PcG assay, implicating CHMP1 in stable gene silencing. Immunocytochemistry, biochemical fractionation, co-localization/recruitment assay, inducible overexpression in HEK293 cells, Xenopus embryo PcG functional assay Journal of cell science Medium 11559747
2012 Loss-of-function mutations in human CHMP1A cause pontocerebellar hypoplasia; CHMP1A-mutant cells show impaired proliferation with increased INK4A expression and loss of normal BMI1-mediated INK4A repression (shown by ChIP). Morpholino knockdown of zebrafish chmp1a produced brain defects partially rescued by INK4A ortholog knockdown, placing CHMP1A upstream of BMI1-mediated INK4A repression in CNS progenitor proliferation. Human genetics (loss-of-function mutations), chromatin immunoprecipitation (ChIP), zebrafish morpholino knockdown with genetic rescue (epistasis) Nature genetics High 23023333
2018 CHMP1A is required for intraluminal vesicle (ILV) formation in multivesicular bodies (MVBs) and for secretion of Sonic Hedgehog (SHH) on a specific extracellular vesicle subtype containing AXL, RAB18, and TMED10 (ART-EVs); Chmp1a null mice show impaired SHH secretion and ILV formation, leading to reduced progenitor proliferation in cortex and cerebellum. Chmp1a null mouse model, electron microscopy (ILV/MVB analysis), EV proteomics, human cerebral organoid knockdown, SHH secretion assay Cell reports High 30044992
2008 Overexpression of Chmp1A in pancreatic ductal tumor cells inhibits cell growth and tumor xenograft formation, and strongly increases protein levels of p53 and phospho-p53; shRNA-mediated silencing promotes anchorage-independent growth and tumor formation, indicating Chmp1A acts as a tumor suppressor partly through p53 signaling. shRNA stable silencing, overexpression in PanC-1 cells, soft agar assay, xenograft assay, Western blot for p53/phospho-p53 Cell cycle (Georgetown, Tex.) Medium 18787405
2011 Overexpression of full-length CHMP1A activates ATM kinase (increased nuclear phospho-ATM) and downstream phospho-p53 in the nucleus; deletion of the nuclear localization signal (NLS) abolishes ATM activation and nuclear localization, indicating nuclear localization is required. ATM inactivation significantly reduces CHMP1A-mediated growth inhibition and p53 phosphorylation, placing ATM downstream of CHMP1A in a growth-suppressive pathway. Overexpression with NLS-deletion mutants, in vitro ATM kinase assay, p53 reporter assay, immunofluorescence co-localization, ATM inhibitor epistasis Cell cycle (Georgetown, Tex.) Medium 21705858
2013 CHMP1A is phosphorylated at Ser179 and Ser182 in its C-terminal region, causing a mobility shift on SDS-PAGE. Ser-to-Ala mutations at these sites do not affect interaction with the binding partner IST1. Site-directed mutagenesis, phosphate-affinity PAGE, co-immunoprecipitation with IST1 Bioscience, biotechnology, and biochemistry Medium 23748770
2014 Drosophila Chmp1 localizes to the late endosome and negatively regulates EGFR (DER) signaling; loss of Chmp1 in the wing causes a cell fate change from intervein to vein and decreases Blistered expression (a readout repressed by DER signaling), consistent with impaired receptor downregulation through the MVB/ESCRT-III pathway. Drosophila genetics (loss-of-function), immunofluorescence localization, genetic interaction analysis with DER pathway regulators, Blistered expression assay Developmental dynamics Medium 24753138
2021 CHMP1A and DPEP1 regulate ferroptosis and cellular iron trafficking; mouse genetic models demonstrate causal roles for both genes in kidney disease, and cellular studies place both in a single ferroptosis pathway. Mouse genetic models (KO), single-cell chromatin accessibility, genome editing (fine mapping), cellular ferroptosis assays Nature communications Medium 34426578
2022 CHMP1A overexpression in renal cell carcinoma cells suppresses mTOR pathway activity, upregulates p53 expression, and induces apoptosis via the MDM2/p53 pathway; p53 knockdown experiments show that p53 elevation is downstream of PI3K/mTOR inhibition by CHMP1A. Overexpression in A498/786-0 cells, Western blot (mTOR/p53/MDM2/Bax/Bcl-2), shRNA-p53 knockdown, colony formation and MTT assays, flow cytometry (apoptosis) Genes & genomics Low 35583792
2022 Drosophila Chmp1 overexpression in the fat body decreases triglyceride storage, while fat-body-specific RNAi knockdown increases triglyceride accumulation; this effect is mediated through control of fat body cell number and size, not food consumption or lipid metabolic enzyme expression. Drosophila tissue-specific RNAi and overexpression (fat body), triglyceride assay, cell number/size measurement Medical sciences (Basel, Switzerland) Low 36649042

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 CHMP1 functions as a member of a newly defined family of vesicle trafficking proteins. Journal of cell science 128 11559748
2001 CHMP1 is a novel nuclear matrix protein affecting chromatin structure and cell-cycle progression. Journal of cell science 100 11559747
2012 CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development. Nature genetics 83 23023333
2018 The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles. Cell reports 81 30044992
2021 A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis. Nature communications 65 34426578
2008 Chmp1A functions as a novel tumor suppressor gene in human embryonic kidney and ductal pancreatic tumor cells. Cell cycle (Georgetown, Tex.) 46 18787405
2018 Anacardic acid inhibits pancreatic cancer cell growth, and potentiates chemotherapeutic effect by Chmp1A - ATM - p53 signaling pathway. BMC complementary and alternative medicine 20 29463243
2012 Chmp1A acts as a tumor suppressor gene that inhibits proliferation of renal cell carcinoma. Cancer letters 16 22261332
2014 The Drosophila Chmp1 protein determines wing cell fate through regulation of epidermal growth factor receptor signaling. Developmental dynamics : an official publication of the American Association of Anatomists 14 24753138
2011 Chromatin modifying protein 1A (Chmp1A) of the endosomal sorting complex required for transport (ESCRT)-III family activates ataxia telangiectasia mutated (ATM) for PanC-1 cell growth inhibition. Cell cycle (Georgetown, Tex.) 14 21705858
1996 Molecular cloning, expression and chromosomal localization of a human gene encoding a 33 kDa putative metallopeptidase (PRSM1). Gene 13 8863740
2004 Molecular characterization of NbCHMP1 encoding a homolog of human CHMP1 in Nicotiana benthamiana. Molecules and cells 11 15179039
2019 miR-17 regulates the proliferation and differentiation of retinal progenitor cells by targeting CHMP1A. Biochemical and biophysical research communications 7 31894018
2022 CHMP1A suppresses the growth of renal cell carcinoma cells via regulation of the PI3K/mTOR/p53 signaling pathway. Genes & genomics 6 35583792
2022 Elucidating the Role of Chmp1 Overexpression in the Transport of Polyamines in Drosophila melanogaster. Medical sciences (Basel, Switzerland) 4 36135830
2022 A novel homozygous CHMP1A variant arising from segmental uniparental disomy causes pontocerebellar hypoplasia type 8. Journal of human genetics 3 36509868
2005 Association analysis of CHMP1.5 genetic variation and bipolar disorder. Psychiatric genetics 3 16094257
2022 The ESCRT-III Protein Chmp1 Regulates Lipid Storage in the Drosophila Fat Body. Medical sciences (Basel, Switzerland) 2 36649042
2013 Identification of phosphorylation sites in the C-terminal region of charged multivesicular body protein 1A (CHMP1A). Bioscience, biotechnology, and biochemistry 2 23748770
2023 Novel bi-allelic variants of CHMP1A contribute to pontocerebellar hypoplasia type 8: additional clinical and genetic evidence. Frontiers in neurology 1 37789895

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