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Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates
Jelena Korac, Veronique Schaeffer, Igor Kovacevic, Albrecht M. Clement, Benno Jungblut, Christian Behl, Janos Terzic, Ivan Dikic


Aggregation of misfolded proteins and the associated loss of neurons are considered 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 recognizes various protein aggregates via its C-terminal coiled-coil domain in a ubiquitin-independent manner. We also show that optineurin depletion significantly increases protein aggregation in HeLa cells and that 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 colocalized with optineurin on protein aggregates and is important in clearance of protein aggregates through the autophagy-lysosome pathway. TBK1 phosphorylates optineurin at serine 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.


  • Funding

    This work was supported by the Cluster of Excellence ‘Macromolecular Complexes’ of the Goethe University Frankfurt [grant number EXC115]; the LOEWE funded OSF network and Gene and Cell Therapy Center; and the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) ERC grant agreement number 250241-LineUb to I.D. J.K. is supported by City of Split scholarship and Boehringer Ingelheim Fonds Travel Grant. B.J. is supported by the Deutsche Forschungsgemeinschaft (Exzellenzcluster 147 “Cardio-Pulmonary Systems”). C.B. is supported by grant from the Fritz-and-Hildegard-Berg-Foundation of the Stifterverband.

  • Accepted October 23, 2012.
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