Cells, the active basis of all life forms, are among the most complex and unique structures known to exist, composed of a multitude of molecules, including proteins, that are responsible for critical functions and roles throughout the body. In fact, within the billions of minute structures that make up these tiny units of life, is a system so intricate that each protein manufactured by a cell must undergo a series of tests to ensure its quality.
Cell biologists at the School of Medicine have taken on the challenge of unraveling this quality control system in an effort to better understand the cell's behavior and its relationship to genetic diseases.
According to Ari H. Helenius, professor and chair of cell biology at the medical school, the production of proteins in the human cell can be compared to a factory assembly line. Each protein must undergo a critical quality control process which detects even the slightest irregularity. "In a factory, before a new product is sent out, it has to pass quality control checks which are necessary to find errors," explains Professor Helenius. "Similarly, when defects are discovered by the cell's quality control, the proteins are noted and given time to correct themselves. If no improvement occurs, the protein is removed and dismantled."
When defective proteins are dismantled, the system recycles the components and reutilizes them within the body. This system, also called architectural editing, depends on the cell's ability to recognize, retain and destroy incompletely assembled proteins, ensuring the structural integrity of protein products. Sometimes, however, a functional protein with a minor defect is rejected, resulting in more damage to the body than if the cell had just the slightly defective protein move through the system.
For instance, some liver diseases occur when proteins in the liver, produced for transport and function in another organ, get caught in the liver's quality control system. These proteins clog the system and cause problems for the liver. This detainment also causes problems for the organ that the protein fails to reach because no other protein is assigned its tasks. However, Professor Helenius says, in many of these cases the protein has only a minor defect which would not affect its performance if it passed the quality control tests and were routed to its intended destination.
When the blueprint for a given protein is defective -- as it is in inherited diseases such as cystic fibrosis, some liver diseases and blood-clotting disorders -- the protein is destroyed, leaving no agent to perform necessary functions. It is this specific type of situation that makes it so important for researchers to find ways of relaxing the stringency by which quality control works and thus, hopefully, eliminating the causes of such diseases, says Professor Helenius.
One of the most intriguing questions confronting Professor Helenius and his colleagues is how the cellular quality control process distinguishes between correctly and incorrectly manufactured proteins. Unlike a factory, which generally has a limited product line, the amount of different proteins produced in a cell numbers in the thousands. Researchers have discovered that there are specific proteins, called "quality control officers," spaced throughout the cell's assembly line. These proteins assist in the manufacturing and maturation process and recognize defects. Some of these "officers" attach themselves to defective proteins until the protein is corrected or destroyed. Others tag incomplete proteins with chemical groups so digesting enzymes know that these proteins are to be dismantled.
Using viral and cellular proteins as their tools, Professor Helenius and his coworkers are now analyzing the rules that govern the cell's quality control system. They are identifying the various molecular players involved, and searching for drugs that could be used to regulate the process in patients with hereditary diseases or infections.
"We need to tell the quality control not to be so picky and to let certain proteins go, even though the cell thinks it's the wrong thing to do. In certain cases, it will cause less difficulty to the body," says Professor Helenius.