| RRC ID |
75908
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| 著者 |
Acker N, Smith H, Devine C, Oltjen SL, Tsiropoulou S, Smit-McBride Z, Lange K, Blacque OE, Matsubara JA, Gordus A, Golden A, Vogel BE.
|
| タイトル |
A complement factor H homolog, heparan sulfation, and syndecan maintain inversin compartment boundaries in C. elegans cilia.
|
| ジャーナル |
Proc Natl Acad Sci U S A
|
| Abstract |
Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly. Canonical disease models suggest that defective interactions between complement factor H (CFH) and cell surface heparan sulfate (HS) result in increased alternative complement pathway activity, cytolytic damage, and tissue inflammation in the retina. Although these factors are thought to contribute to increased disease risk, multiple studies indicate that noncanonical mechanisms that result from defective CFH and HS interaction may contribute to the progression of AMD as well. A total of 60 ciliated sensory neurons in the nematode Caenorhabditis elegans detect chemical, olfactory, mechanical, and thermal cues in the environment. Here, we find that a C. elegans CFH homolog localizes on CEP mechanosensory neuron cilia where it has noncanonical roles in maintaining inversin/NPHP-2 within its namesake proximal compartment and preventing inversin/NPHP-2 accumulation in distal cilia compartments in aging adults. CFH localization and maintenance of inversin/NPHP-2 compartment integrity depend on the HS 3-O sulfotransferase HST-3.1 and the transmembrane proteoglycan syndecan/SDN-1. Defective inversin/NPHP-2 localization in mouse and human photoreceptors with CFH mutations indicates that these functions and interactions may be conserved in vertebrate sensory neurons, suggesting that previously unappreciated defects in cilia structure may contribute to the progressive photoreceptor dysfunction associated with CFH loss-of-function mutations in some AMD patients.
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| 巻・号 |
118(16)
|
| 公開日 |
2021-4-20
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| DOI |
10.1073/pnas.2016698118
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| PII |
2016698118
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| PMID |
33859044
|
| PMC |
PMC8072366
|
| MeSH |
Animals
Caenorhabditis elegans / metabolism
Caenorhabditis elegans Proteins / metabolism
Cilia / metabolism
Complement Factor H / metabolism*
Complement Factor H / physiology
Heparitin Sulfate / metabolism*
Heparitin Sulfate / physiology
Macular Degeneration / metabolism
Macular Degeneration / physiopathology
Neurons / metabolism
Retina / metabolism*
Transcription Factors / metabolism
|
| リソース情報 |
| 線虫 |
tm734 |
