Optineurin – lending a helping hand to clear protein aggregates

The accumulation of misfolded proteins is a hallmark of many neurodegenerative diseases including Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). Misfolded proteins are usually degraded by the ubiquitin–proteasome system, but they can also activate autophagy. Optineurin is present in protein inclusions in various neurodegenerative diseases and has recently been shown to be an autophagy adaptor, but its role in the aggregation process is unclear. On page 580, Ivan Dikic and colleagues used two aggregation-prone protein models to investigate the role of optineurin; a short fragment of the protein huntingtin (htt) with an extended polyglutamine (polyQ) mutation and mutations of superoxide dismutase1 (SOD1), which are used as models of HD and ALS, respectively. They show that optineurin recognizes htt and SOD1 aggregates though its C-terminal domain in a manner that is independent of ubiquitin and participates in their degradation. Mechanistically, the authors demonstrate that optineurin-mediated degradation is regulated by its phosphorylation by TANK1 binding kinase 1, which results in recruitment of the autophagy machinery. They also find that depletion of optineurin in HeLa cells leads to a substantial increase in protein aggregation, and silencing of the zebrafish orthologue results in fish with a motor axonopathy phenotype similar to that of ALS. These results support a protective role of optineurin in neurodegenerative disorders associated with intracellular protein aggregation.