Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis
| العنوان: | Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis |
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| المؤلفون: | Hirotaka Takahashi, Fuminori Tokunaga, Hidefumi Ito, Izuho Hatada, Takashi Ayaki, Seshiru Nakazawa, Kiyoko Kamei, Ryuichiro Ishitani, Ryohei Ishii, Kazuhiro Iwai, Izumi Takeyoshi, Tatsuya Sawasaki, Daisuke Oikawa, Hiroyuki Takeda, Hideshi Kawakami, Osamu Nureki |
| المصدر: | Nature Communications, Vol 7, Iss 1, Pp 1-14 (2016) Nature Communications |
| بيانات النشر: | Springer Nature, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Models, Molecular, 0301 basic medicine, Ubiquitin binding, Cell death in the nervous system, General Physics and Astronomy, Apoptosis, Cell Cycle Proteins, Crystallography, X-Ray, Gene Knockout Techniques, Ubiquitin, Transcription Factor TFIIIA, Amyotrophic lateral sclerosis, Caspase, Optineurin, Inclusion Bodies, Multidisciplinary, biology, NF-kappa B, Recombinant Proteins, I-kappa B Kinase, Cell biology, Receptors, Tumor Necrosis Factor, Type I, Caspases, Signal transduction, Protein Binding, Signal Transduction, Science, Caspase 8, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Stress signalling, Protein Domains, medicine, Humans, X-ray crystallography, Amyotrophic Lateral Sclerosis, HEK 293 cells, Ubiquitination, Membrane Transport Proteins, General Chemistry, medicine.disease, HEK293 Cells, 030104 developmental biology, Amino Acid Substitution, Mutation, biology.protein, Mutant Proteins, HeLa Cells |
| الوصف: | Optineurin (OPTN) mutations cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and glaucoma. Although the ALS-associated E478G mutation in the UBAN domain of OPTN reportedly abolishes its NF-κB suppressive activity, the precise molecular basis in ALS pathogenesis still remains unclear. Here we report that the OPTN-UBAN domain is crucial for NF-κB suppression. Our crystal structure analysis reveals that OPTN-UBAN binds linear ubiquitin with homology to NEMO. TNF-α-mediated NF-κB activation is enhanced in OPTN-knockout cells, through increased ubiquitination and association of TNF receptor (TNFR) complex I components. Furthermore, OPTN binds caspase 8, and OPTN deficiency accelerates TNF-α-induced apoptosis by enhancing complex II formation. Immunohistochemical analyses of motor neurons from OPTN-associated ALS patients reveal that linear ubiquitin and activated NF-κB are partially co-localized with cytoplasmic inclusions, and that activation of caspases is elevated. Taken together, OPTN regulates both NF-κB activation and apoptosis via linear ubiquitin binding, and the loss of this ability may lead to ALS. Mutations in optineurin are associated with neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, the authors report the structure of the ubiquitin binding domain of optineurin, which binds linear ubiquitin with homology to NEMO, and explore the function of this domain. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c3713297484dcafbaa08a921ff77f3c9 http://hdl.handle.net/2433/226349 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c3713297484dcafbaa08a921ff77f3c9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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