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ZIRC
ZFIN ID: ZDB-PUB-121205-54
Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates
Korac, J., Schaeffer, V., Kovacevic, I., Clement, A.M., Jungblut, B., Behl, C., Terzic, J., and Dikic, I.
Date: 2013
Source: Journal of Cell Science   126(2): 580-592 (Journal)
Registered Authors: Jungblut, Benno
Keywords: none
MeSH Terms:
  • Animals
  • Autophagy/physiology
  • Disease Models, Animal
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurodegenerative Diseases/genetics
  • Neurodegenerative Diseases/metabolism*
  • Phosphorylation
  • Protein Binding
  • Transcription Factor TFIIIA/metabolism*
  • Ubiquitin/metabolism*
  • Zebrafish
PubMed: 23178947 Full text @ J. Cell Sci.
FIGURES
ABSTRACT

Aggregation of misfolded proteins and the associated loss of neurons are considered as a hallmark of numerous neurodegenerative diseases. Optineurin is present in protein inclusions observed in various neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, Creutzfeld-Jacob disease and Pick's disease. Optineurin deletion mutations have also been described in ALS patients. However, the role of optineurin in mechanisms of protein aggregation remains unclear. In this report, we demonstrate that optineurin recognized various protein aggregates via its C-terminal coiled-coil domain in a ubiquitin-independent manner. We also show that optineurin depletion significantly increase protein aggregation in HeLa cells and morpholino-silencing of the optineurin ortholog in zebrafish causes the motor axonopathy phenotype similar to a zebrafish model of ALS. A more severe phenotype is observed when optineurin is depleted in zebrafish carrying ALS mutations. Furthermore, TANK1 binding kinase 1 (TBK1) is co-localized with optineurin on protein aggregates and is important in clearance of protein aggregates through the autophagy-lysosome pathway. TBK1 phosphorylates optineurin at position Ser-177 and regulates its ability to interact with autophagy modifiers. This study provides evidence for a ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates as well as additional relevance for TBK1 as an upstream regulator of the autophagic pathway.

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