Falling apart under pressure is generally considered undesirable, but for a cellular organelle called the Golgi apparatus, such a breakdown is all part of the plan. Researchers at the Weizmann Institute of Science have discovered a surprising pool of protein-degrading “machinery” known as proteasomes hanging around the outer membranes of the Golgi apparatus. Their findings, which were recently reported in Nature Communications, suggest that breaking apart under stress might be a normal control mechanism for this organelle; and these findings may open the door to the possibility of treating cancers and other diseases in which Golgi malfunction or dysregulation play a role.
The research, which was co-led by Drs. Avital Eisenberg-Lerner, Ron Benyair and Noa Hizkiahou from the lab of Dr. Yifat Merbl in Weizmann’s Immunology Department, identified a novel role for cellular proteasomes in controlling the Golgi. Benyair, who initiated this study, had stumbled upon a peculiar observation, namely, the discovery of a “private” supply of proteasomes for the Golgi. Merbl says: “We were then curious to know exactly what these protein-degrading machines were doing there.”
Some 30 percent of all cellular proteins pass through the Golgi, which means that this small organelle exerts a great deal of control over what happens in our bodies. It acts as a “way-station” for most proteins that are outward-bound – whether to the cell’s outer membrane or outside the cell. Eisenberg-Lerner, a senior scientist in Merbl’s lab, explains that the Golgi is built on the “Ikea store” plan: Proteins must transverse its entire set of compartments. Along the way, they may pick up trappings – sugars and such – and at the end of the last corridor, they are assigned transport vehicles to take them to the cell membrane or beyond.
In the multiple myeloma cells, causing Golgi disintegration led to cell death
To pinpoint exactly what the Golgi-localized proteasomes were taking apart, the scientists first hypothesized that in addition to the two well-known causes of Golgi disintegration – impending cell division or cell death – excess stress might also provoke the proteasomes to action. To simulate stress the scientists overloaded the Golgi with proteins, creating a logjam, or they disrupted the additions of sugars to the traversing proteins. This enabled them to show that stress indeed caused the Golgi to break down. The researchers then revealed that the proteasomes were taking out specific structural supports – a tethering protein called GM130 that is normally associated with the Golgi membranes. “Snipping” GM130 made the entire structure unstable and, ultimately, unable to remain intact.
The researchers reasoned that because protein secretion and thus Golgi function vary widely between cell types, the destructive mechanism they discovered should have different effects on different cells. The team chose to focus on multiple myeloma cells, a cancer of the plasma cells – cells that secrete antibodies – in which this process is taken to new levels by dysregulation until the overworked Golgis becomes misshapen from the effort.
The experiments revealed that, in contrast to normal cells in which the Golgi reassembles soon after disintegration, in the multiple myeloma cells, causing Golgi disintegration led to cell death. This finding gave the team a new research clue: Could they, for example, use this new knowledge to manipulate such cancerous cells into dying? By experimenting with mouse models of multiple myeloma, the researchers succeeded in recreating Golgi logjams that led to lethal stress in the cancer cells. But when they blocked the proteasomes’ function, the Golgi remained intact even under stress. And when they added extra GM130 to the stressed Golgi, basically replacing the degraded proteins, the scientists found they could reduce cell death, even in highly stressful conditions. In other words, the proteasomes’ degradation of GM130 is, indeed, the cause of Golgi dispersion and cell death. This finding suggested to the research team that targeting the Golgi apparatus could present a new approach to killing multiple myeloma cells.
Testing this idea in the lab, the researchers administered the drug that they had shown would induce Golgi stress in mouse models of multiple myeloma, finding that it drastically reduced the number of cancerous cells in the bone marrow and spleen of these mice within a week. “Because the Golgi apparatus is so overactive in multiple myeloma, this drug was highly targeted – it only affected the cancerous cells, prompting them to initiate cell death proceedings, whereas the healthy cells easily recovered from the Golgi disintegration,” says Eisenberg-Lerner.
“We think that the Golgi disintegration may act as a sort of sensor in the cell,” says Merbl. “This organelle rapidly breaks down when there is stress, but then it pauses. If the stress passes, for example, if the problem was just a protein ‘logjam,’ it can reassemble and all is well; but if the stress continues or gets worse, the aberration in Golgi function and its dispersal becomes toxic to the cell.”
“There are implications for certain cancers, but these findings may advance research into treating any number of diseases,” she adds. “For example, the Golgi is disrupted in the most common neurodegenerative diseases. If we could find a way to control this disruption, we might be able to control the progression of numerous diseases involving protein secretion.”
Proteasomes, the Golgi and disease
The regulation of the Golgi apparatus and of proteasomes is widely studied, in part because their dysregulation plays a role in many diseases, including certain cancers, autoimmune diseases and neurodegeneration. Merbl and her lab group focus on the proteasomes, which, altogether in the cell, break down some 70% of the cell’s proteins. Recently, she and her group developed a “dumpster-diving” method of looking inside proteasomes; this method enabled them to observe a distinct pattern of protein breakdown in an autoimmune disease. Proteasomes had been thought, until relatively recently, to be all-purpose, but the past decade provided examples where these cellular complexes played a role in the quality control of protein fidelity in several organelles such as the mitochondria and endoplasmic reticulum. Finding them next to the Golgi, an organelle that plays an important regulatory role for all the outward-bound proteins in a cell, raises quite a few new questions about the way that the regulator is, in itself, regulated, and suggests that further research is likely to turn up many more connections to disease processes.
Dr. Yifat Merbl’s research is supported by the Moross Integrated Cancer Center; Dr. Celia and Dr. Lutz Zwillenberg-Fridman; and the Peter and Patricia Gruber Awards. Dr. Merbl is the incumbent of the Leonard and Carol Berall Career Development Chair.