دورية أكاديمية
Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62
| العنوان: | Germline variants of ATG7 in familial cholangiocarcinoma alter autophagy and p62 |
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| المؤلفون: | Stephanie U. Greer, Jiamin Chen, Margret H. Ogmundsdottir, Carlos Ayala, Billy T. Lau, Richard Glenn C. Delacruz, Imelda T. Sandoval, Sigrun Kristjansdottir, David A. Jones, Derrick S. Haslem, Robin Romero, Gail Fulde, John M. Bell, Jon G. Jonasson, Eirikur Steingrimsson, Hanlee P. Ji, Lincoln D. Nadauld |
| المصدر: | Scientific Reports, Vol 12, Iss 1, Pp 1-15 (2022) |
| بيانات النشر: | Nature Portfolio, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Medicine LCC:Science |
| مصطلحات موضوعية: | Medicine, Science |
| الوصف: | Abstract Autophagy is a housekeeping mechanism tasked with eliminating misfolded proteins and damaged organelles to maintain cellular homeostasis. Autophagy deficiency results in increased oxidative stress, DNA damage and chronic cellular injury. Among the core genes in the autophagy machinery, ATG7 is required for autophagy initiation and autophagosome formation. Based on the analysis of an extended pedigree of familial cholangiocarcinoma, we determined that all affected family members had a novel germline mutation (c.2000C>T p.Arg659* (p.R659*)) in ATG7. Somatic deletions of ATG7 were identified in the tumors of affected individuals. We applied linked-read sequencing to one tumor sample and demonstrated that the ATG7 somatic deletion and germline mutation were located on distinct alleles, resulting in two hits to ATG7. From a parallel population genetic study, we identified a germline polymorphism of ATG7 (c.1591C>G p.Asp522Glu (p.D522E)) associated with increased risk of cholangiocarcinoma. To characterize the impact of these germline ATG7 variants on autophagy activity, we developed an ATG7-null cell line derived from the human bile duct. The mutant p.R659* ATG7 protein lacked the ability to lipidate its LC3 substrate, leading to complete loss of autophagy and increased p62 levels. Our findings indicate that germline ATG7 variants have the potential to impact autophagy function with implications for cholangiocarcinoma development. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2045-2322 |
| Relation: | https://doaj.org/toc/2045-2322 |
| DOI: | 10.1038/s41598-022-13569-4 |
| URL الوصول: | https://doaj.org/article/07556fe7ab554218a24d01d6e4b51299 |
| رقم الأكسشن: | edsdoj.07556fe7ab554218a24d01d6e4b51299 |
| قاعدة البيانات: | Directory of Open Access Journals |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 20452322 |
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| DOI: | 10.1038/s41598-022-13569-4 |