The Cellular Chamber of Doom

Alfred l. Goldberg, Stephen J. Elledge and H. Wade Harper

Scientific American, January 2001

Every minute of every day a scene straight out of an Indiana Jones plays out in all our cells. One second a hapless protein is tooling along just trying to do its job. The next instant it is branded for destruction and gets sucked into a dark tunnel, where it is quickly cut to pieces. Unlike Indiana Jones, for the protein there is no escape. Inside the chamber of doom, the protein is stretched out like a medieval prisoner on the rack and fed through a series of enzymatic knives that deliver the Death of a Thousand Cuts. A few seconds later, the remnants emerge from the tunnel, only to be pounced on and chewed up further by simpler enzymes.

One might think that this intracellular drama is insignificant (except, perhaps, to the unfortunate protein). But scientists in many laboratories, such as our own, are now finding that these molecular abattoirs, called proteasomes, are crucial players in pathways that regulate an entire repertory of cellular processes. A typical cell in the body has roughly 30,000 proteasomes. When they malfunction - whether overeagerly gobbling important proteins of failing to destroy those that are damaged or improperly formed – diseases can ensue. Some viruses, such as HIV, have even developed the means to manipulate protein degradation by proteasomes for their own ends. Indeed, several of the next generation drugs to treat cancer and other dire diseases are expected to consist of chemical compounds that act on proteasomes and the pathways that feed proteins into proteasomes. Several biopharmaceutical companies are now studying compounds that inhibit the proteasome pathway; two such potential drugs are already in clinical trials in humans.

Turnover Is Fair Play

Proteins are the very fabric of which cells are made. Some proteins also act as enzymes, the molecular workhorses that drive the chemical reactions of life. The types of proteins a cell produces depend on which of its genes are active at any given time. Genes encode how 20 amino acids are assembled into chains of various combinations. The chains fold into compact coils and loops to become different kinds of proteins, each with a specific function determined by its shape and chemistry.

What happens when proteins are no longer needed or fail to fold correctly? For years, scientists presumed that the lion’s share of protein degradation occurs in lysosomes, bags of digestive enzymes present in most cells of the body. But in the early 1970s A. Goldberg showed that cells lacking lysosomes, such as bacteria and immature red blood cells, can nonetheless destroy abnormal proteins rapidly. What is more, the process requires energy, whereas other degradative processes do not.

He and his colleagues were able to get the energy-requiring degradation process to work in test tubes, which enables several research groups in the late 1970s and throughout the 1980s to discover the enzymes responsible. Eventually, in 1988, it was found that the proteins are broken down by large, multi-enzyme complexes that Goldberg’s group named proteasomes.

Proteasomes were so named because they contain many proteases, enzymes that cut proteins into chunks. But proteasomes are 100 times larger and more complex than other proteases. Once a protein is laid on the doormat of a proteasome, it is taken inside the particle and ultimately disassembled like a Tinker Toy into amino acids that can be reassembled later into other proteins. Most proteins are replaced every few days, even in cells that themselves divide rarely, such as those in the liver or nervous systems. And different proteins are degraded at widely differing rates: some have half-lives as short as 20 minutes, whereas others in the same cell may last for days or weeks. These rates of breakdown can change drastically according to changing conditions in our bodies.

At first glance, such continuous destruction of cell constituents appears very wasteful, but it serves a number of essential functions. Degrading a crucial enzyme or regulatory protein, for example, is a common mechanism that cells use to slow or stop a biochemical reaction. On the other hand, many cellular processes are activated by the degradation of a critical inhibitory protein, just as water flows out of a bathtub when you remove the stopper. This rapid elimination of regulatory proteins is particularly important in timing the transitions between the stages of the cycle that drive cell division.

Protein degradation also plays special roles in the overall regulation of body metabolism. In times of need, such as malnourishment or disease, the proteasome pathway becomes more active in our muscles, providing amino acids that can be converted into glucose and burned for energy. This excessive protein breakdown accounts for the muscle wasting and weakness seen in starving individuals and those with advanced cancer, AIDS and untreated diabetes.

Our immune system, in its constant search to eliminate virus-infected or cancerous cells, also depends on proteasomes to generate the flags that distinguish such dangerous cells. Although cell proteins are usually degraded all the way to amino acids, a few fragments composed of 8 to 10 amino acids are released by proteasomes, captured and ultimately displayed on the cell’s surface, where the immune system can monitor whether they are normal or abnormal. Indeed, in disease states and in certain tissues such as the spleen and lymph nodes, specialized types of proteasomes termed immunoproteasomes are produced that enhance the efficiency of this surveillance mechanism.

Protein breakdown by proteasomes also serves as a kind of cellular quality-control system that prevents the accumulation of aberrant – and potentially toxic – proteins. Bacterial and mammalian cells selectively destroy proteins with highly abnormal conformations that can arise from mutation, errors in synthesis or damage.

The degradation of abnormal proteins is important in a number of human genetic diseases. In various hereditary anemias, a mutant gene leads to the production of abnormal hemoglobin molecules, which do not fold properly and are rapidly destroyed by proteasomes after synthesis. Similarly, cystic fibrosis is caused by a mutation in the gene encoding a porelike protein that moves chloride across a cell’s outer membrane. The sticky mucus that builds up in the lungs and other organs of people with cystic fibrosis results from the lack of normal chloride transporters.

Still other diseases could result in part from the failure of abnormal proteins to be degraded by proteasomes. Scientists are finding, for example, that clumps of misfolded proteins accumulate in association with proteasomes in certain nerve cells, or neurons, in the brains of people with neurodegenerative disorders, such as Parkinson’s, Huntington’s and Alzheimer’s diseases. Why the neurons of individuals stricken with these maladies fail to degrade the abnormal proteins is a burgeoning field of research.

Answer the questions.

1. What happens when proteasomes malfunction?
2. Can cells without lysosomes destroy abnormal proteins?
3. Is a continuous destruction of cell constituents wasteful?
4. How can the loss of muscle tissue in cancer and HIV patients be accounted for?
5. What conditions depend on degradation of abnormal proteins?