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

Nat Commun. 2016 Aug 24:7:12547. doi: 10.1038/ncomms12547.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Amyotrophic Lateral Sclerosis / etiology*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Apoptosis
  • Caspases / metabolism
  • Cell Cycle Proteins
  • Crystallography, X-Ray
  • Gene Knockout Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / metabolism
  • Inclusion Bodies / metabolism
  • Membrane Transport Proteins
  • Models, Molecular
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation*
  • NF-kappa B / metabolism
  • Protein Binding
  • Protein Domains
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Transcription Factor TFIIIA / chemistry
  • Transcription Factor TFIIIA / genetics*
  • Transcription Factor TFIIIA / metabolism*
  • Ubiquitination

Substances

  • Cell Cycle Proteins
  • IKBKG protein, human
  • Membrane Transport Proteins
  • Mutant Proteins
  • NF-kappa B
  • OPTN protein, human
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Proteins
  • Transcription Factor TFIIIA
  • I-kappa B Kinase
  • Caspases