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Seek and Destroy

June 24, 2014
Ubiquibodies combine the specificity of antibodies with the destruction signal of ubiquitinization. Stand by for targeted destruction of disease-causing proteins in the cell

Proteins in a cell that are aged or otherwise damaged are recycled via the ubiquitin-proteasome pathway (UPP). The doomed protein is first tagged with a protein called ubiquitin, which acts like a molecular sign reading “destroy me”, and then broken down by the proteasome, which is the cell’s recycling center. This catabolism generates amino acids for re-use within the cell.

What if, thought scientists at Cornell University, led by Matthew DeLisa, you could direct the UPP towards proteins of particular interest? Might it be possible to selectively destroy proteins in the cell, such as those involved in cancer development or the pathology underlying Alzheimer’s Disease?

Their research, published in the Journal of Biological Chemistry (DOI:10.1074/jbc. M113.544825 (2014)) shows that it can be done. Not only was it possible to harness the UPP to eliminate a target protein, the method was simple and tunable, neither of which are hallmarks of the standard genetic engineering toolkit.

The addition of ubiquitin to proteins in cells (the process is called ubiquitination) involves three types of enzymes, known as E1, E2 and E3 and the researchers modified one particular E3 enzyme called CHIP, replacing its binding domain with an engineered antibody fragment. In a proof-of-principle experiment, CHIP was modified with an antibody fragment that recognizes the enzyme beta-galactosidase. When the modified CHIP was expressed alongside the target enzyme in a human cell line, the levels of beta-galactosidase went down: the higher the level of expression of modified CHIP, the lower the level of beta-galactosidase.

The group call modified CHIPs “ubiquibodies”, combining elements of ubiquitination and antibody. They have great potential. “Our ability to redirect whatever protein you want to the proteasome is now made possible simply by swapping out different binding proteins with specificity for targets of interest to the researcher,” said DeLisa.

Ubiquibodies also provide a new method to study the function and kinetics of proteins. Current gene knockout technologies are all or nothing but with an ubiquibody it becomes possible to look at what happens when, say, 50 percent of the copies of a particular protein are removed.

The technology could also prove to be a useful platform for future drug therapies. In a cancer cell in which a certain protein has been identified as contributing to the disease, the ubiquibody could reduce or eliminate the protein from within by targeting that specific protein only. DeLisa’s lab is already exploring this therapeutic potential with experiments on target proteins present in Alzheimer’s disease, cancer and Parkinson’s disease.