title: Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan.|Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
authors.forename: Seshiru
authors.initials: S
authors.lastname: Nakazawa
authors.affiliation: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan.|Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Oikawa
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Ryohei
authors.identifier: 0000-0003-2486-1393
authors.initials: R
authors.lastname: Ishii
authors.affiliation: Department of Neurology, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Wakayama 641-8510, Japan.|Department of Neurology, Kyoto University Graduate School of Medicine, Sakyo-ku, Shogoin, Kyoto 606-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ayaki
authors.affiliation: Proteo-Science Center, Ehime University, Matsuyama, Ehime 790-8577, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Proteo-Science Center, Ehime University, Matsuyama, Ehime 790-8577, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Ishitani
authors.affiliation: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kamei
authors.affiliation: Department of Thoracic and Visceral Organ Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Takeyoshi
authors.affiliation: Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Hideshi
authors.identifier: 0000-0002-1405-0901
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
authors.affiliation: Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan.
authors.forename: Izuho
authors.initials: I
authors.lastname: Hatada
authors.affiliation: Proteo-Science Center, Ehime University, Matsuyama, Ehime 790-8577, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawasaki
authors.affiliation: Department of Neurology, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Wakayama 641-8510, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
authors.affiliation: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan.|Department of Pathobiochemistry, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Tokunaga
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D002479:Inclusion Bodies / Q000378:metabolism; D026901:Membrane Transport Proteins; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D035582:Transcription Factor TFIIIA / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; C491731:IKBKG protein, human; D026901:Membrane Transport Proteins; D050505:Mutant Proteins; D016328:NF-kappa B; C409460:OPTN protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D035582:Transcription Factor TFIIIA; D051550:I-kappa B Kinase; D020169:Caspases