論文 - 詳細
| RRC ID | 81118 |
|---|---|
| 著者 | Cui Y, Yu X, Bao J, Ping X, Shi S, Huang Y, Yin Q, Yang H, Chen R, Yao K, Chen X, Shentu X. |
| タイトル | Lens autophagy protein ATG16L1: a potential target for cataract treatment. |
| ジャーナル | Theranostics |
| Abstract |
Rationale: Cataract is the leading cause of blindness and low vision worldwide, yet its pathological mechanism is not fully understood. Although macroautophagy/autophagy is recognized as essential for lens homeostasis and has shown potential in alleviating cataracts, its precise mechanism remains unclear. Uncovering the molecular details of autophagy in the lens could provide targeted therapeutic interventions alongside surgery. Methods: We monitored autophagic activities in the lens and identified the key autophagy protein ATG16L1 by immunofluorescence staining, Western blotting, and transmission electron microscopy. The regulatory mechanism of ATG16L1 ubiquitination was analyzed by co-immunoprecipitation and Western blotting. We used the crystal structure of E3 ligase gigaxonin and conducted the docking screening of a chemical library. The effect of the identified compound riboflavin was tested in vitro in cells and in vivo animal models. Results: We used HLE cells and connexin 50 (cx50)-deficient cataract zebrafish model and confirmed that ATG16L1 was crucial for lens autophagy. Stabilizing ATG16L1 by attenuating its ubiquitination-dependent degradation could promote autophagy activity and relieve cataract phenotype in cx50-deficient zebrafish. Mechanistically, the interaction between E3 ligase gigaxonin and ATG16L1 was weakened during this process. Leveraging these mechanisms, we identified riboflavin, an E3 ubiquitin ligase-targeting drug, which suppressed ATG16L1 ubiquitination, promoted autophagy, and ultimately alleviated the cataract phenotype in autophagy-related models. Conclusions: Our study identified an unrecognized mechanism of cataractogenesis involving ATG16L1 ubiquitination in autophagy regulation, offering new insights for treating cataracts. |
| 巻・号 | 14(10) |
| ページ | 3984-3996 |
| 公開日 | 2024-1-1 |
| DOI | 10.7150/thno.93864 |
| PII | thnov14p3984 |
| PMID | 38994020 |
| PMC | PMC11234268 |
| MeSH | Animals Autophagy* / drug effects Autophagy-Related Proteins* / metabolism Cataract* / drug therapy Cataract* / metabolism Cell Line Disease Models, Animal Humans Lens, Crystalline* / drug effects Lens, Crystalline* / metabolism Riboflavin / pharmacology Ubiquitination / drug effects Zebrafish* |
| IF | 8.579 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | SRA 01/04(RCB1591) |