Affinage

TRAPPC11

Trafficking protein particle complex subunit 11 · UniProt Q7Z392

Length
1133 aa
Mass
128.9 kDa
Annotated
2026-04-28
21 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRAPPC11 is a subunit of the TRAPP III complex that functions in anterograde membrane trafficking, lipid-linked oligosaccharide (LLO) biosynthesis, and protein N-glycosylation. Its foie gras and gryzun domains mediate binding to other TRAPP subunits; mutations in these domains disrupt Golgi architecture, delay ER-to-Golgi and Golgi-to-plasma membrane transport, and cause hypoglycosylation of multiple glycoproteins including LAMP1, LAMP2, ICAM-1, and α-dystroglycan (PMID:23830518, PMID:26912795, PMID:38564972). TRAPPC11 depletion independently reduces LLO levels and triggers an unfolded protein response and lipid droplet accumulation, while disruption of its carboxy terminus additionally impairs autophagic flux (PMID:26912795, PMID:31575891). Biallelic loss-of-function mutations cause a congenital disorder of glycosylation manifesting as muscular dystrophy (dystroglycanopathy), hepatic steatosis, and neurodegeneration (PMID:26322222, PMID:34648194).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2013 High

    Establishing that TRAPPC11 is required for TRAPP complex integrity and post-Golgi membrane trafficking answered whether this large subunit has a discrete role beyond ER-to-Golgi transport, revealing that foie gras domain mutations specifically delay Golgi exit and alter LAMP1/LAMP2 glycosylation.

    Evidence Co-immunoprecipitation, cargo trafficking kinetics, and glycoprotein blotting in patient fibroblasts carrying defined foie gras or gryzun domain mutations

    PMID:23830518

    Open questions at the time
    • Whether TRAPPC11's trafficking role is separable from a direct glycosylation function was unknown
    • Structural basis for foie gras versus gryzun domain contributions to TRAPP binding unresolved
    • Whether Golgi exit delay is the primary cause of glycoprotein alterations or a secondary effect was not determined
  2. 2015 Medium

    Demonstrating that loss of full-length TRAPPC11 causes congenital muscular dystrophy with hepatic steatosis established TRAPPC11 as a disease gene with multi-organ physiological consequences.

    Evidence Immunoblotting confirming protein absence, mRNA splicing analysis, and muscle/liver biopsy histology in patients with compound heterozygous mutations

    PMID:26322222

    Open questions at the time
    • Mechanism linking TRAPPC11 loss to lipid accumulation in liver was not resolved
    • Whether steatosis results from trafficking defects or glycosylation defects was unclear
  3. 2016 High

    Revealing that TRAPPC11 is required for LLO biosynthesis—independent of other TRAPP subunits—resolved the question of whether TRAPPC11 has a glycosylation-specific function beyond vesicle trafficking, showing that its loss reduces LLO pools, triggers the UPR, and promotes lipid droplet accumulation.

    Evidence siRNA knockdown in human cells with LLO quantification, UPR reporter assays, pharmacological phenocopy of terpenoid pathway inhibition, and zebrafish trappc11 mutant analysis

    PMID:26912795

    Open questions at the time
    • Direct molecular mechanism by which TRAPPC11 controls LLO synthesis (enzymatic target or membrane platform) was not identified
    • Whether the UPR is a cause or consequence of lipid droplet accumulation was not distinguished
  4. 2016 Medium

    A splice mutation reducing full-length TRAPPC11 confirmed that both ER-to-Golgi arrival and Golgi exit are TRAPPC11-dependent, extending the trafficking defect model to both anterograde steps.

    Evidence Fluorescent cargo trafficking assays and LAMP1 glycosylation analysis in patient fibroblasts

    PMID:27707803

    Open questions at the time
    • Whether residual truncated protein retains partial function was not assessed
    • Contribution of each trafficking step to overall glycosylation impairment not quantified
  5. 2018 Medium

    Linking TRAPPC11 mutations to α-dystroglycan hypoglycosylation established TRAPPC11-opathy as a dystroglycanopathy, answering whether the glycosylation defect extends to the functionally critical O-mannosyl glycans of α-dystroglycan.

    Evidence IIH6 immunofluorescence and western blotting for glycosylated α-dystroglycan combined with live-cell trafficking assays in patient fibroblasts

    PMID:29855340

    Open questions at the time
    • Whether α-dystroglycan hypoglycosylation is secondary to N-glycosylation/LLO defects or reflects an independent pathway was not resolved
    • Quantitative relationship between trafficking delay severity and degree of α-dystroglycan glycosylation loss not established
  6. 2019 Medium

    Demonstrating that carboxy-terminal truncation of TRAPPC11 causes autophagic flux defects—not seen with the gryzun missense variant alone—revealed a domain-specific role for the C-terminus in autophagy, separable from its trafficking and glycosylation functions.

    Evidence Autophagic flux assays, ER-to-Golgi and Golgi exit assays, and ER-resident glycoprotein glycosylation in fibroblasts with defined bi-allelic variant combinations

    PMID:31575891

    Open questions at the time
    • Whether the autophagy defect is mediated through TRAPP III's known role in autophagosome formation or an independent mechanism was not resolved
    • Identity of C-terminal interaction partners mediating autophagy function unknown
  7. 2021 Medium

    Showing universal α-dystroglycan hypoglycosylation in skeletal muscle, Purkinje cells, and dentate neurons in TRAPPC11-mutant patients established that the glycosylation defect is not tissue-restricted, explaining the neurological phenotype as a central glycosylation disorder.

    Evidence IIH6 immunofluorescence on post-mortem brain and muscle tissue, membrane trafficking assays in fibroblasts, neuropathological examination

    PMID:34648194

    Open questions at the time
    • Whether neuronal degeneration is cell-autonomous or secondary to extracellular matrix dysfunction was not determined
    • Whether other glycoproteins beyond α-dystroglycan contribute to the CNS phenotype remains unknown
  8. 2024 Medium

    Confirming defective ER-to-Golgi transport and decreased expression of LAMP2 and ICAM-1 across additional TRAPPC11 mutations consolidated the classification of TRAPPC11-opathy as a congenital disorder of glycosylation (CDG) with broad glycoprotein impact.

    Evidence Membrane trafficking assays and western blotting for glycoproteins in patient fibroblasts

    PMID:38564972

    Open questions at the time
    • Full glycoproteomic characterization of hypoglycosylation targets has not been performed
    • Whether glycosylation correction rescues the trafficking phenotype (or vice versa) is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct molecular mechanism by which TRAPPC11 controls LLO biosynthesis—whether through organizing dolichol-pathway enzymes at ER membranes, modulating terpenoid flux, or another mechanism—remains unresolved, and the structural basis for domain-specific contributions of the foie gras, gryzun, and C-terminal regions to trafficking, glycosylation, and autophagy has not been determined.
  • No enzymatic target or direct binding partner for LLO pathway regulation identified
  • No high-resolution structure of TRAPPC11 within the TRAPP III complex
  • Causal hierarchy between trafficking defects and glycosylation defects not experimentally separated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005794 Golgi apparatus 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 1
Complex memberships
TRAPP III

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 TRAPPC11 mutations (p.Gly980Arg in the gryzun domain and p.Ala372_Ser429del in the foie gras domain) impair binding of TRAPPC11 to other TRAPP complex components and disrupt Golgi apparatus architecture; the foie gras domain deletion causes normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface, and leads to alterations of lysosomal membrane glycoproteins LAMP1 and LAMP2. Co-immunoprecipitation, marker trafficking experiments, immunofluorescence of Golgi markers, western blotting of LAMP1/LAMP2 in patient fibroblasts with defined mutations American journal of human genetics High 23830518
2016 TRAPPC11 is required for lipid-linked oligosaccharide (LLO) biosynthesis and protein N-glycosylation; depletion of TRAPPC11 (but not other TRAPP components) in human cells causes protein hypoglycosylation associated with reduced LLO levels and compensatory upregulation of the terpenoid/dolichol biosynthetic pathway, leading to a stressed unfolded protein response and lipid droplet accumulation. Zebrafish trappc11 mutant analysis, siRNA knockdown of TRAPPC11 in human cells, LLO level measurement, UPR reporter assays, pharmacological inhibition of terpenoid/LLO synthesis, patient fibroblast analysis Molecular biology of the cell High 26912795
2016 A TRAPPC11 splice mutation (c.1893+3A>G) causes incomplete exon skipping, dramatic reduction of full-length TRAPPC11 protein, hypoglycosylation of LAMP1, delayed arrival of marker proteins at the Golgi, and delayed release from the Golgi to the plasma membrane in patient fibroblasts. Western blotting, membrane trafficking assays with fluorescent cargo markers in patient fibroblasts, mRNA analysis Journal of medical genetics Medium 27707803
2015 TRAPPC11 is a component of the multiprotein TRAPP complex involved in endoplasmic reticulum-to-Golgi trafficking; loss of full-length TRAPPC11 protein (due to compound heterozygous mutations including a novel splice-site mutation causing frameshift/truncation) causes congenital muscular dystrophy with steatosis, demonstrating a physiological role in multiple tissues. Immunoblotting showing absence of full-length TRAPPC11, mRNA splicing analysis, muscle and liver biopsy histology Skeletal muscle Medium 26322222
2018 TRAPPC11 mutations are associated with hypoglycosylation of α-dystroglycan; compound heterozygous TRAPPC11 mutations (c.851A>C and c.965+5G>T) cause abnormal membrane trafficking in patient fibroblasts, linking membrane trafficking defects to dystroglycanopathy for the first time. Immunofluorescence and western blotting for α-dystroglycan glycosylation, live cell membrane trafficking analysis in patient fibroblasts Skeletal muscle Medium 29855340
2019 TRAPPC11 functions in membrane trafficking and autophagy as a component of TRAPP III; variants affecting the carboxy terminus (frameshift p.Asp1127Valfs*47) cause defects in ER-to-Golgi transport, Golgi exit, and glycosylation of an ER-resident glycoprotein, while the compound heterozygous (foie gras deletion + C-terminal frameshift) combination additionally causes autophagic flux defects not seen with the missense variant alone, highlighting the critical role of the extreme carboxy terminus. Membrane trafficking assays, glycosylation assays (ER-resident glycoprotein), autophagic flux assay in patient fibroblasts with defined bi-allelic variants Scientific reports Medium 31575891
2021 TRAPPC11 is important for complex integrity and anterograde membrane transport from the ER to the ER-Golgi intermediate compartment; mutations cause universal hypoglycosylation of α-dystroglycan in skeletal muscle and brain (including Purkinje cells and dentate neurons), with neuropathology resembling N-linked congenital disorders of glycosylation. Membrane trafficking assays in patient fibroblasts, immunofluorescence with IIH6 antibody for α-dystroglycan glycosylation in muscle and post-mortem brain, neuropathological examination Neuropathology and applied neurobiology Medium 34648194
2023 TRAPPC11 deficiency impairs mitochondrial function: patient fibroblasts/muscle from individuals with the c.1287+5G>A founder variant show decreased mitochondrial ATP production capacity and alterations in mitochondrial network architecture. Mitochondrial ATP production assays and mitochondrial network morphology analysis in patient-derived cells Journal of medical genetics Low 37197784
2024 TRAPPC11 mutations cause defective ER-to-Golgi transport and decreased expression of LAMP2 and ICAM-1 glycoproteins, further supporting TRAPPC11-opathy as a congenital disorder of glycosylation (CDG) with muscular dystrophy. Membrane trafficking assays and western blotting for glycoprotein expression in patient fibroblasts Molecular genetics and metabolism Medium 38564972

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons? Human molecular genetics 241 11773003
2013 Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability. American journal of human genetics 89 23830518
2000 Identification of GRY-RBP as an apolipoprotein B RNA-binding protein that interacts with both apobec-1 and apobec-1 complementation factor to modulate C to U editing. The Journal of biological chemistry 85 11134005
2018 TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of α-dystroglycan and muscular dystrophy. Skeletal muscle 48 29855340
2015 Congenital muscular dystrophy with fatty liver and infantile-onset cataract caused by TRAPPC11 mutations: broadening of the phenotype. Skeletal muscle 43 26322222
2016 A novel TRAPPC11 mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima. Journal of medical genetics 39 27707803
2001 Two-hybrid cloning identifies an RNA-binding protein, GRY-RBP, as a component of apobec-1 editosome. Biochemical and biophysical research communications 35 11352648
2016 trappc11 is required for protein glycosylation in zebrafish and humans. Molecular biology of the cell 34 26912795
2017 Siblings With Mutations in TRAPPC11 Presenting With Limb-Girdle Muscular Dystrophy 2S. Journal of clinical neuromuscular disease 22 28827486
2021 TRAPPC11-related muscular dystrophy with hypoglycosylation of alpha-dystroglycan in skeletal muscle and brain. Neuropathology and applied neurobiology 18 34648194
2019 Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein. Scientific reports 14 31575891
2023 Expanding the phenotypic spectrum of TRAPPC11-related muscular dystrophy: 25 Roma individuals carrying a founder variant. Journal of medical genetics 9 37197784
2018 Novel TRAPPC11 Mutations in a Chinese Pedigree of Limb Girdle Muscular Dystrophy. Case reports in genetics 9 30105108
2024 TRAPPC11-CDG muscular dystrophy: Review of 54 cases including a novel patient. Molecular genetics and metabolism 8 38564972
2021 Digenic Variants in the TTN and TRAPPC11 Genes Co-segregating With a Limb-Girdle Muscular Dystrophy in a Han Chinese Family. Frontiers in neuroscience 8 33746696
2024 Screening and identification of Paenibacillus polymyxa GRY-11 and its biological control potential against apple replant disease. Folia microbiologica 7 39352682
2021 Whole-Exome Sequencing and hiPSC Cardiomyocyte Models Identify MYRIP, TRAPPC11, and SLC27A6 of Potential Importance to Left Ventricular Hypertrophy in an African Ancestry Population. Frontiers in genetics 6 33679876
2010 Expression of G-Ry derived from the potato (Solanum tuberosum L.) increases PVY(O) resistance. Journal of agricultural and food chemistry 4 20481626
2024 Large TRAPPC11 gene deletions as a cause of muscular dystrophy and their estimated genesis. Journal of medical genetics 1 38955476
2021 Corrigendum: Digenic Variants in the TTN and TRAPPC11 Genes Co-segregating With a Limb-Girdle Muscular Dystrophy in a Han Chinese Family. Frontiers in neuroscience 0 33967689
2020 Publisher Correction: Characterization of three TRAPPC11 variants suggests a critical role for the extreme carboxy terminus of the protein. Scientific reports 0 33173071