Marking and removing harmful substances
All living cells have to constantly monitor their own components and dispose of those that are potentially harmful, such as misfolded proteins or invading microbes, when necessary. This process is known as selective autophagy. To ensure that only the correct cellular components are eliminated, they are marked with chains of ubiquitin molecules. These chains interact with selective autophagy receptors that also bind with the autophagy mechanisms.
"One core protein in these cellular logistics is optineurin," explains Winklhofer. "It specifically identifies misfolded proteins, damaged mitochondria, and invading bacteria, and signals to the autophagy system that these disruptive factors have to be removed." It was previously unclear how this identification and organization process works in detail.
How the connection to the break-down machinery is formed
The research team in Bochum has shown that, after binding to ubiquitin chains, optineurin forms condensates that facilitate the efficient connection to the autophagy machinery. Condensates are reaction spaces in cells that form through phase separation. The formation of optineurin-ubiquitin condensates requires phosphorylation of optineurin by the protein TBK1 (tank-binding kinase 1), as phosphorylated optineurin can bind better to ubiquitin chains.
The LC3 protein, which plays an important role in the autophagy process, is also enriched in the condensates. Through the binding of optineurin to LC3, the components to be broken down are precisely directed to membranes where they are packed into autophagosomes and can then be digested in lysosomal organelles.
Proteins lose their function through mutations
"Interestingly, mutations in the optineurin and TBK1 genes are associated with familial forms of neurodegenerative diseases," says Dr. Georgina Herrera, first author of the publication. These disease-causing mutations lead to a loss of function in optineurin and TBK1. Protein aggregates can then accumulate in nerve cells.
"The current study provides mechanistic insight into these processes," says Winklhofer. "A detailed understanding of the break-down and clearance of harmful cellular components could inform new treatment approaches in the future, especially for neurodegenerative diseases."
