Your cells do something akin to editing a major motion picture every day. They take raw footage in the form of genes and turn it into sophisticated proteins with lots of bells and whistles. Many different professionals play a role in this process, including the exon junction complex (EJC), which resembles a movie studio executive. HMS researchers recently turned the spotlight on the EJC.
Discovered in 2000, the EJC is finally beginning to gain recognition. A paper by HMS professor John Blenis and postdoctoral researcher Xiaoju Max Ma in the April 18 issue of Cell shows one way the EJC regulates protein production, solving part of a major metabolic mystery.
The EJC joins the production team early in the editing process, when the cell decides which scenes to include in a protein. Initially, the cell makes a copy of the entire gene, transcribing a long stretch of DNA that contains extraneous sequences, resembling clips, which end up on the cutting room floor. The cell stitches together the remaining sequences, which are called exons, and deposits an EJC near each splice site. The resulting EJC-dotted chain—termed a messenger RNA—comprises the template for a specific protein.
The messenger RNA is shuttled from the nucleus to the cytoplasm, where it awaits translation—the energy-intensive process of stringing together amino acids to form the backbone of the protein.
A movie studio doesn’t continue with costly post-production on a film if funds are drying up. Similarly, a cell doesn’t initiate translation if nutrients are scarce. Blenis and Ma’s data suggests that the EJC helps the cell decide whether to move forward with this energy-demanding step, and keeps the rest of the production team in the loop. The EJC appears to communicate with a well-known nutrient-sensing pathway, relaying messages about energy levels to the translation initiation machinery.
The researchers made this connection while probing a protein called SKAR, which receives signals from a known nutrient-sensing hub (called mTOR). They discovered that SKAR binds to the EJC and transmits signals to the tip of the messenger RNA, where translation begins, providing a mechanistic missing link between nutrient sensing and protein production, which is necessary for proper cell growth.
“We didn’t expect the EJC to be involved,” says Ma. “This study provides the first evidence that splicing is connected with nutrient sensing and cellular metabolism, as EJCs are added to the messenger RNA during splicing.”
In other words, splicing increases translational control by bringing the EJC executive into the mix. That executive consults with the cell’s energy experts before giving the green light to the translation initiation machinery and promoting cell growth through protein production.
“Max has uncovered an important link between metabolic processes and protein synthesis,” says Blenis. “ This research has implications for aberrant growth regulation, which underlies human diseases ranging from cancer to diabetes.”
This research is supported by the National Institutes of Health and the Leukemia and Lymphoma Society.
