Speeding the Cellular Waste Disposal System

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Image: Flickr - Michael Kohli
The ubiquitin-proteasome system (UPS) is a critical element of the cellular machinery, responsible for removing unwanted proteins. Target proteins, which may be misfolded, oxidised or simply no longer required, are marked for degradation by attachment of ubiquitin chains. The ubiquitinated proteins are then recognised by the proteasome and subjected to proteolytic cleavage. Failure of the UPS leads to a build up of damaged or misfolded proteins that may result in cellular toxicity.

Accumulation of misfolded proteins is a feature of a number of human disorders including Alzheimer’s, Parkinson’s and Creutzfeldt-Jakob diseases. Upregulation of the UPS is therefore of interest for potential therapy of these disorders.

Usp14 crystal structure
Complex of Usp14 (grey spheres) with ubiquitin-aldehydye (blue ribbon). PDB ID=2AYO

A team from Harvard Medical School has been investigating the role of Usp14, a de-ubiquitinating enzyme associated with the proteasome. They found that Usp14 is able to inhibit the proteasomal degradation of ubiquitin-protein conjugates both in vitro and in cells. A catalytically inactive variation of Usp14 had reduced inhibitory properties, suggesting that Usp14 mediates its effects by cleavage of ubiquitin from the substrate proteins.

The team identified a small molecule inhibitor of Usp14 using high-throughput screening and treatment of cultured cells with this compound enhanced the degradation of proteasome substrates associated with neurodegeneration. The compound also accelerated the degradation of oxidised proteins and improved cellular resistance to oxidative stress.

The study, published in Nature, sheds light on a poorly understood aspect of the UPS – the control of the speed of protein degradation. The authors suggest that inhibition of Usp14 may be a strategy to address a variety of human diseases where accumulation of aberrant proteins is a factor.

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