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-?B suppressive activity, the precise molecular basis in ALS pathogenesis still remains unclear. Here we report that the OPTN-UBAN domain is crucial for NF-?B suppression. Our crystal structure analysis reveals that OPTN-UBAN binds linear ubiquitin with homology to NEMO. TNF-?-mediated NF-?B 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-?-induced apoptosis by enhancing complex II formation. Immunohistochemical analyses of motor neurons from OPTN-associated ALS patients reveal that linear ubiquitin and activated NF-?B are partially co-localized with cytoplasmic inclusions, and that activation of caspases is elevated. Taken together, OPTN regulates both NF-?B activation and apoptosis via linear ubiquitin binding, and the loss of this ability may lead to ALS.

SUBMITTER: Nakazawa S 

PROVIDER: S-EPMC4999505 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature