IRIC - Institute for Research in Immunology and Cancer

Published on December 13, 2019

To create proteins from the information contained in genes, cells use messenger RNAs, which carry the genetic information to the ribosomes (the translation machinery) where this messenger RNA gets converted into proteins. For this conversion to take place, most RNAs must bind a protein called “eIF4E.” eIF4E recognizes messenger RNAs which have a special modification at the front of the RNA known as a “cap”, which stimulates their movement to the translation machinery and ultimately converts messenger RNA into its active form, protein. The cap structure is a centre piece for RNA regulation and is extremely simple; consisting of a modified nucleotide which interacts with eIF4E at what is known as its “cap-binding site”. It was thought that this is the only way that eIF4E can bind to RNAs and engage the translation machinery to convert mRNA to proteins.

Dr. Borden’s team has shown for the first time that the cap-binding site of eIF4E can be co-opted by a protein (about a hundred times larger than the cap). This viral protein, when directly conjugated to large pieces of RNA, can recruit them to the machinery via binding the cap site of eIF4E and converts these RNAs to protein. Thus, instead of using the nucleotide cap, the virus uses a protein for the same job.

Chance discovery

The discovery is the result of work carried out on VPg, a viral protein that attacks potatoes! By infecting a potato plant, the virus injects hundreds of copies of the VPg protein, many of which are attached to a messenger RNA that the virus hopes to convert into protein in order to make viral proteins that allow the virus to multiply. VPg plays a vital role in the operation by taking the protein-making machinery hostage. It achieves this purpose by engaging eIF4E, a protein so essential to life on Earth that it can be found in both animals and in plants. Dr. Borden’s discovery that a protein, which is structurally different to the cap, can recruit RNA to the protein synthesis machinery has never been observed before. This observation suggests there could be a completely different mechanism to engage this machinery for conversion of RNAs into proteins. Whether this is limited to viral proteins or can occur in uninfected cells remains to be determined.

Having determined the three-dimensional structure of VPg, Dr. Borden’s team hypothesized that human proteins with a similar three-dimensional structure may also engage eIF4E. They searched databases by structural homology and identified a human motor protein, KIF11/EG5, a protein studied extensively by Dr. Benjamin Kwok of IRIC. Up until now, EG5 had no link to eIF4E, but their studies showed that they were right: KIF11/EG5 also binds to the cap-binding site of eIF4E, supporting the notion that this new potential mechanism for the control and engagement of eIF4E could be conserved from plants to humans. This work must now be developed further by Dr. Borden and her team.

Gaining a better understanding of eIF4E regulation mechanisms is of great interest because along with playing a vital role in the cell, this protein is abnormally overexpressed in several cancers where its overabundance contributes to transforming normal cells into cancer cells. In previous work, Dr. Borden’s team, and her collaborators, discovered that eIF4E is a very promising therapeutic target for treating certain leukemias.