In an emotionally difficult situation, it’s easy to feel as though we are “eating ourselves up from the inside.” In humans, this is no more than a psychological feeling, but for cells in our body, getting eaten from the inside can really happen. Every one of our cells is uploaded with a special “program” that instructs the cell to abort if it becomes a threat to the body – if it begins to turn cancerous, for example. This phenomenon of cellular suicide can occur in two different ways. The most commonly known is named “apoptosis” (in Greek: “falling off,” like leaves from a deciduous tree). In apoptosis, the cell produces toxic proteins that cause it to break apart. Cells that kill themselves in this way are “eaten” by neighboring cells. The second cellular suicide method, called autophagy, occurs when the cell literally eats itself from within. Malfunctions in these self-destruct programs may result in diseases such as cancer.
Prof. Adi Kimchi, Head of the Molecular Genetics Department, and research student Sharon Reef recently identified a novel protein that tells the cancerous cell to choose the self-eating method of suicide. In research that was published in the journal Molecular Cell, Kimchi and Reef discovered that this new protein is actually a shortened version of a previously known protein that usually causes apoptosis. These two proteins are in fact encoded by the same gene, even though each instructs the cancerous cell to commit suicide in a different way. The scientists proved that the shorter version of the protein, due to the missing segment, carries out its activity in an area of the cell completely different from that used by the longer protein. Consequently, autophagy is
triggered instead of apoptosis.
The process of autophagy is based on the concept of “recycling bins”: double-membraned sac-like structures that actively develop in the cells. Especially during times of starvation, when food is lacking, these bins are able to recycle some of the cell’s contents, providing it with extra food and energy. But under certain circumstances, the recycling bins work in overdrive mode, resulting in self-eating to the point of death. The question arose: Is the observed autophagy – that triggered by the novel protein – a survival mechanism or its opposite, an agent of self-destruction?
To answer the question, Kimchi and Reef, together with Einat Zalckvar and Shani Bialik of the Molecular Genetics Department and Prof. Moshe Oren and Ohad Shifman of the Molecular Cell Biology Department, silenced two genes that are known to be necessary for assembling the sac-like autophagic “recycling bins.” They discovered that reducing the occurrence of autophagy via gene silencing increased the survival of cells and thus concluded that the formation of the membrane-bound sacs in this case spells total degradation for the cells’ contents.
But why have two different suicide mechanisms developed in cells? Kimchi suggests that the autophagy track is a sort of back-up plan, in case the cancer cell fails – for a variety of possible reasons – to sacrifice itself by apoptosis. By employing a back-up plan, the cell continues to ensure the prevention of the spread of cancer. Now the scientists plan to check if their understanding is correct, or whether autophagy is an independent process, unrelated to the cell's earlier failed attempts to commit apoptosis.
Prof. Adi Kimchi’s research is supported by the Clore Center for Biological Physics; the Leo and Julia Forchheimer Center for Molecular Genetics; the Levine Institute of Applied Science; the Jeans-Jacques Brunschwig Fund for the Molecular Genetics of Cancer; the Joseph and Bessie Feinberg Foundation; the Flight Attendant Medical Research Institute; the Anne P. Lederer Research Institute; the Lombroso Prize for Cancer Research; the Ruth and Samuel Rosenwasser Charitable Fund; and the Jacqueline Seroussi Foundation Israel. Prof. Kimchi is the incumbent of the Helena Rubinstein Professorial Chair in Cancer Research.
Anyone who’s had the experience of putting machinery back together and having a part left over knows that some parts are more essential than others. Prof. Zvulun Elazar of the Biological Chemistry Department has used this principle to identify, for the first time, two sites on a particular yeast protein that are indispensable for protein recognition. Without these recognition sites, the process of assembling the “recycling bins” needed for cellular self-eating can’t take place.
For the protein to carry out its activity, a specific, complementary protein needs to recognize and “plug” into one of its “sockets” – an action that initiates a cascade of events. By removing various socket-like structures one at a time from the protein and seeing how this affected the overall working of the autophagic machine, Elazar and his research team were able to isolate the specific site the second protein must recognize and hook up to. When this site was missing, that protein remained unplugged, leaving the cellular recycling machinery idle. They also found a second site on the protein that appears to be necessary for autophagic activity, although how it works needs to be studied further.
Autophagy in mammalian cells has significant associations with neurodegenerative diseases, heart disease, cancer, program-med cell death, and bacterial and viral infections. Because the autophagic recycling system found in yeast is similar to that in mammals, this research could provide crucial insight for further studies into the malfunctioning of cellular machinery and its consequences.
This research, which was published in EMBO Reports, was conducted with Ph.D. students Nira Amar of the Biological Chemistry Department and Gila Lustig of the Biological Regulation Department, in collaboration with Dr. Yoshinobu Ichimura and Prof.Yoshinori Ohsumi of the National Institute for Basic Biology, Japan.
Prof. Zvulun Elazar’s research is supported by the Philip M. Klutznick Fund for Research; Mr. and Mrs. Stanley Chais, Beverly Hills, CA; and Mr. and Mrs. Mitchell Caplan, Bethesda, MD.