ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2015
Genetic ablation of N-linked glycosylation reveals two key folding pathways for R345W fibulin-3, a secreted protein associated with retinal degeneration.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 36 citations in OpenAlex.
- Antisense oligonucleotide allele-specific targeting of EFEMP1 in a patient-derived model of Doyne honeycomb retinal dystrophy.Molecular therapy. Nucleic acids · 2026Article
- Genetic removal of Nlrp3 protects against age-related and R345W Efemp1-induced basal laminar deposit formation.Cell death & disease · 2025Article
- A spectrum of cysteine mutations in fibulin-3 highlight its disulfide bonding complexity and potential to induce ER stress.Scientific reports · 2025Article
- Alternative Splicing of FBLN2 Generates a Prometastatic Extracellular Matrix in Gastrointestinal Cancers by Determining N-Glycosylation of Fibulin 2.Genes to cells : devoted to molecular & cellular mechanisms · 2025Article
- GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology.JCI insight · 2024Article
- Exploring ocular fibulin-3 (EFEMP1): Anatomical, age-related, and species perspectives.Biochimica et biophysica acta. Molecular basis of disease · 2024Article
- GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology.bioRxiv : the preprint server for biology · 2023Article
- Complement factor B is critical for sub-RPE deposit accumulation in a model of Doyne honeycomb retinal dystrophy with features of age-related macular degeneration.Human molecular genetics · 2023Article
- Clinically-identified C-terminal mutations in fibulin-3 are prone to misfolding and destabilization.Scientific reports · 2021Article
- In-depth Site-specific Analysis of N-glycoproteome in Human Cerebrospinal Fluid and Glycosylation Landscape Changes in Alzheimer's Disease.Molecular & cellular proteomics : MCP · 2021Article
- Fibulin-3 knockout mice demonstrate corneal dysfunction but maintain normal retinal integrity.Journal of molecular medicine (Berlin, Germany) · 2020Article
- Transcriptome analysis of neural progenitor cells derived from Lowe syndrome induced pluripotent stem cells: identification of candidate genes for the neurodevelopmental and eye manifestations.Journal of neurodevelopmental disorders · 2020Article
- Expression of R345W-Fibulin-3 Induces Epithelial-Mesenchymal Transition in Retinal Pigment Epithelial Cells.Frontiers in cell and developmental biology · 2020Article
- Role of Epithelial-Mesenchymal Transition in Retinal Pigment Epithelium Dysfunction.Frontiers in cell and developmental biology · 2020Review
- The matrix protein Fibulin-3 promotes KISS1R induced triple negative breast cancer cell invasion.Oncotarget · 2018Article
- Neuroprotective Strategy in Retinal Degeneration: Suppressing ER Stress-Induced Cell Death via Inhibition of the mTOR Signal.International journal of molecular sciences · 2017Review
- Mapping wild-type and R345W fibulin-3 intracellular interactomes.Experimental eye research · 2016Review
- Evidence of Alternative Cystatin C Signal Sequence Cleavage Which Is Influenced by the A25T Polymorphism.PloS one · 2016Article
- A local complement response by RPE causes early-stage macular degeneration.Human molecular genetics · 2015Article
- Differential tolerance of 'pseudo-pathogenic' tryptophan residues in calcium-binding EGF domains of short fibulin proteins.Experimental eye research · 2015Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
An R345W mutation in the N-glycoprotein, fibulin-3 (F3), results in inefficient F3 folding/secretion and higher intracellular F3 levels. Inheritance of this mutation causes the retinal dystrophy malattia leventinese. N-Linked glycosylation is a common cotranslational protein modification that can regulate protein folding efficiency and energetics. Therefore, we explored how N-glycosylation alters the protein homeostasis or proteostasis of wild-type (WT) and R345W F3 in ARPE-19 cells. Enzymatic and lectin binding assays confirmed that WT and R345W F3 are both primarily N-glycosylated at Asn249. Tunicamycin treatment selectively reduced R345W F3 secretion by 87% (vs. WT F3). Genetic elimination of F3 N-glycosylation (via an N249Q mutation) caused R345W F3 to aggregate intracellularly and adopt an altered secreted conformation. The endoplasmic reticulum (ER) chaperones GRP78 (glucose-regulated protein 78) and GRP94 (glucose-regulated protein 94), and the ER lectins calnexin and calreticulin were identified as F3 binding partners by immunoprecipitation. Significantly more N249Q and N249Q/R345W F3 interacted with GRP94, while substantially less N249Q and N249Q/R345W interacted with the ER lectins than their N-glycosylated counterparts. Inhibition of GRP94 ATPase activity reduced only N249Q/R345W F3 secretion (by 62%), demonstrating this variant's unique reliance on GRP94 for secretion. These observations suggest that R345W F3, but not WT F3, requires N-glycosylation to acquire a stable, native-like structure.
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