“How will this system work if I remove one vital piece?” For researchers studying living organisms, answering this question is often a major component of their research. The system in question may be as small as three molecules or as large as a whole animal. Depending on the system and the nature of its components different tools are brought to bear. The clearest results are obtained when a single component is removed completely and specifically but in practice this is difficult to achieve. A major stumbling block is often the timing of different techniques – can researchers quickly remove the component at a time of their choosing. For example, a researcher may wish to observe the differences between cells that contain or lack a specific protein. Current techniques can interrupt the production of new protein molecules but do not affect proteins that are already present. If those molecules are stable they can complicate analysis for an extended period. A newly-developed technique combines specificity and complete removal with much faster action compared with existing methods.
Trim-Away: An Unprecedented New Tool
The new method is called Trim-Away, a reference to its use of the Trim21 protein to direct degradation of other proteins. Researchers in Germany and the UK have demonstrated that a natural process used by cells to degrade infectious agents can also cause the rapid degradation of specifically targeted proteins within the cell. Trim21 functions to trigger a rapid response when a particle such as a virus is recognized by antibodies in the bloodstream before it infects a cell. Trim21 binds to the antibodies and causes cellular machinery to degrade whatever protein the antibody has bound. The scientists reasoned that this machinery could be used to specifically degrade any targeted protein if it was bound by an antibody in the cytoplasm. Antibodies can have incredible specificity for protein targets and can be introduced into cells by standard techniques. In developing the Trim-Away method the researchers demonstrated that specific protein targets can be rapidly degraded by forcing antibodies into cells. Excitingly, they found that degradation occurs in minutes rather than hours or days as is seen with other techniques.
For researchers studying the systems of interacting proteins within cells the Trim-Away method is a valuable new tool with the ability to leverage the vast number of existing antibodies. The specificity of antibodies may also create potential therapeutic uses for this technique. Some diseases such as Huntington’s are thought to be caused by specific proteins changing their shape into a toxic form. An antibody that discriminates between the healthy and toxic conformations may work with the Trim-Away method to clear out the harmful protein. Unlike CRISPR/Cas9 and RNAi, Trim-Away is able to expend a targeted protein from any cell, even non-dividing primary cells, those that resist DNA- and RNA-targeting methods. Further development of this technique will prove valuable both in the laboratory, in the realm of genome editing, and the clinic.
- Image Credit: MRC Laboratory of Molecular Biology
- Cell: A Method for the Acute and Rapid Degradation of Endogenous Proteins