Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis

Seshiru Nakazawa, Daisuke Oikawa, Ryohei Ishii, Takashi Ayaki, Hirotaka Takahashi, Hiroyuki Takeda, Ryuichiro Ishitani, Kiyoko Kamei, Izumi Takeyoshi, Hideshi Kawakami, Kazuhiro Iwai, Izuho Hatada, Tatsuya Sawasaki, Hidefumi Ito (), Osamu Nureki () and Fuminori Tokunaga ()
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Seshiru Nakazawa: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University
Daisuke Oikawa: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University
Ryohei Ishii: Graduate School of Science, The University of Tokyo
Takashi Ayaki: Wakayama Medical University
Hirotaka Takahashi: Proteo-Science Center, Ehime University
Hiroyuki Takeda: Proteo-Science Center, Ehime University
Ryuichiro Ishitani: Graduate School of Science, The University of Tokyo
Kiyoko Kamei: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University
Izumi Takeyoshi: Gunma University Graduate School of Medicine
Hideshi Kawakami: Research Institute for Radiation Biology and Medicine, Hiroshima University
Kazuhiro Iwai: Graduate School of Medicine, Kyoto University
Izuho Hatada: Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University
Tatsuya Sawasaki: Proteo-Science Center, Ehime University
Hidefumi Ito: Wakayama Medical University
Osamu Nureki: Graduate School of Science, The University of Tokyo
Fuminori Tokunaga: Laboratory of Molecular Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12547

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