Korac, J., Schaeffer, V., Kovacevic, I., Clement, A.M., Jungblut, B., Behl, C., Terzic, J., and Dikic, I. (2013) Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates. Journal of Cell Science. 126(2):580-592.
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.