SVIP regulates Z variant alpha-1 antitrypsin retro-translocation by inhibiting ubiquitin ligase gp78
| العنوان: | SVIP regulates Z variant alpha-1 antitrypsin retro-translocation by inhibiting ubiquitin ligase gp78 |
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| المؤلفون: | Mariana E. Kirst, Chen Liu, George Marek, Karina Krotova, Farshid N. Rouhani, Nazli Khodayari, Mark L. Brantly, Rejean liqun Wang |
| المصدر: | PLoS ONE PLoS ONE, Vol 12, Iss 3, p e0172983 (2017) |
| بيانات النشر: | Public Library of Science, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, lcsh:Medicine, medicine.disease_cause, Endoplasmic Reticulum, Biochemistry, Animal Cells, Medicine and Health Sciences, Small interfering RNAs, lcsh:Science, chemistry.chemical_classification, Mutation, Multidisciplinary, Secretory Pathway, biology, Endoplasmic Reticulum Stress, Cell biology, Ubiquitin ligase, Transport protein, Amino acid, Precipitation Techniques, Nucleic acids, Protein Transport, Liver, Cell Processes, Hyperexpression Techniques, Cellular Structures and Organelles, Cellular Types, Anatomy, Research Article, Context (language use), Endoplasmic-reticulum-associated protein degradation, DNA construction, Transfection, Research and Analysis Methods, Real-Time Polymerase Chain Reaction, Cell Line, 03 medical and health sciences, medicine, Gene Expression and Vector Techniques, Genetics, Immunoprecipitation, Humans, Molecular Biology Techniques, Non-coding RNA, Molecular Biology, Molecular Biology Assays and Analysis Techniques, Endoplasmic reticulum, lcsh:R, Biology and Life Sciences, Membrane Proteins, Cell Biology, Phosphate-Binding Proteins, Gene regulation, Receptors, Autocrine Motility Factor, 030104 developmental biology, chemistry, Membrane protein, alpha 1-Antitrypsin, Plasmid Construction, Vacuoles, biology.protein, Hepatocytes, RNA, lcsh:Q, Gene expression, Carrier Proteins |
| الوصف: | Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by early-onset emphysema and liver disease. The most common disease-causing mutation is a single amino acid substitution (Glu/Lys) at amino acid 342 of the mature protein, resulting in disruption of the 290-342 salt bridge (an electrophoretic abnormality defining the mutation [Z allele, or ZAAT]), protein misfolding, polymerization, and accumulation in the endoplasmic reticulum of hepatocytes and monocytes. The Z allele causes a toxic gain of function, and the E3 ubiquitin ligase gp78 promotes degradation and increased solubility of endogenous ZAAT. We hypothesized that the accumulation of ZAAT is influenced by modulation of gp78 E3 ligase and SVIP (small VCP-interacting protein) interaction with p97/VCP in ZAAT-expressing hepatocytes. We showed that the SVIP inhibitory effect on ERAD due to overexpression causes the accumulation of ZAAT in a human Z hepatocyte-like cell line (AT01). Overexpression of gp78, as well as SVIP suppression, induces gp78-VCP/p97 interaction in AT01 cells. This interaction leads to retro-translocation of ZAAT and reduction of the SVIP inhibitory role in ERAD. In this context, overexpression of gp78 or SVIP suppression may eliminate the toxic gain of function associated with polymerization of ZAAT, thus providing a potential new therapeutic approach to the treatment of AATD. |
| اللغة: | English |
| تدمد: | 1932-6203 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f9b5594a28f36f4999bca6e7c4c0f73c http://europepmc.org/articles/PMC5354272 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f9b5594a28f36f4999bca6e7c4c0f73c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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