The ubiquitin proteolytic system

Thank you very much for the invitation. The American Thoracic Society this year is celebrating its centennial, which is really wonderful, and it’s a good reason for a party. What I am going to tell you today is actually not about the ubiquitin system so much but about the evolution of the idea of proteolysis—where we started, where we are today, and where we are heading. Haifa (Figure 1), the San Diego of the Middle East, is a city that resides on the easternmost shore of the Mediterranean; it is a beautiful city looking from Mt. Carmel into the bay. It is here that we started our journey into the world of protein degradation. To place things in context, it is important to define which type of proteolysis we are studying. The body destroys proteins in several levels (Figure 2). The first level is obviously the gastrointestinal tract, and the purpose of this process is simple. In the gastrointestinal tract, we are destroying proteins in order to remove antigenicity. We cannot introduce foreign proteins into the body because they challenge our immune system; therefore, we have to remove them, to disintegrate them into their basic ingredients, the amino acids. One additional reason for digestion in the intestinal tract is to derive energy, and we derive energy from our dietary proteins. We can think of the gastrointestinal tract as an extracorporeal proteolytic organ. This process occurs out of our body in an open tube that starts in our mouth and ends in the anus; it is physically external to the body. Once we move into the body, we are still in the extracellular compartment, but intracorporeal. Here we need to be more controlled, because in the gastrointestinal tract, the process is indiscriminatory, and every single protein that enters the small intestine is digested in a nonspecific manner. Inside the body, things are different. More controlled systems must exist. In the circulation, we are already encountering a controlled system: for example, the blood coagulation system. This system is a cascade of proteolytic reactions. One inactive factor is activated to become an active protease. It then cleaves a downstream factor in a limited manner; this is then converted from an inactive protease into an active protease, and this active