Science Daily: Cell Energy Sensor Mechanism Discovered

Johns Hopkins and National Taiwan University researchers have discovered more details about how an energy sensing "thermostat" protein determines whether cells will store or use their energy reserves.

In a report in the Feb. 9 edition of Nature, the researchers showed that a chemical modification on the thermostat protein changes how it's controlled. Without the modification, cells use stored energy, and with it, they default to stockpiling resources. When cells don't properly allocate their energy supply, they can die off or become cancerous. The Johns Hopkins team focused especially on enzymes that add or remove so-called acetyl groups from protein molecules.

"Understanding how cells are affected by adding acetyl groups to proteins, particularly those involved in energy use, is important because there is increasing use of drugs that block acetyl-removing enzymes for treatment of cancer and neurodegenerative diseases," says Jef Boeke, Ph.D., professor of molecular biology, genetics and oncology, and director of the High Throughput Biology Center at the Johns Hopkins University School of Medicine. "Blocking acetyl-removing enzymes turns on anticancer genes that help fight cancer; however, it is not known what other genes and cellular processes may also be affected by these treatments."

To determine which enzymes remove acetyl chemical groups from which proteins, the researchers engineered human cells with reduced levels of each of 12 enzymes known to remove acetyl chemical groups. In each of these cell lines, they then turned down each of about 20,000 genes and used a DNA "chip" to identify which genes were affected by reduced levels of the acetyl-removing enzymes. The DNA chip highlighted a specific interaction between the thermostat protein, AMP-activated protein kinase (AMPK), and one of the acetyl-removing enzymes, HDAC1.

With less HDAC, AMPK was turned "off," presumably because it retains its acetyl group, the researchers concluded. AMPK acts like an energy thermostat because when energy levels are low in the cell, AMPK kick-starts processes that use the cell's energy reserves and cuts off reactions that store energy. On the other hand, when the cell has plenty of energy, AMPK turns off, causing energy in the form of sugar and fats being stored for later use.

Because the HDAC1 protein turned on AMPK, the researchers presumed there would be a corresponding acetyl-adding enzyme to specifically turn off AMPK. To find this enzyme, they extracted AMPK protein from eight different cell lines, each with reduced levels of a type of acetyl-adding enzyme. They found that AMPK in cells with reduced levels of this acetyl-adding enzyme, called p300, was less acetylated than in cells containing normal amounts of p300...

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