Our behavior is a product not just of who we are, but of where we are and who we’re with. That goes also for a protein called BID that plays a central role in our cells’ life cycles. Institute scientists studying this protein are finding that it can split its activities between two different sites in the cell, and its different actions in each can literally be a matter of life or death. Their findings may be important for understanding a number of disorders, from a rare genetic disease to such metabolic syndromes as obesity and diabetes.
When Prof. Atan Gross
and his research team in the Biological Regulation Department began investigating BID in lab dishes, they discovered that BID steers a cell that is in trouble – from damaged DNA, for instance – toward either altruistic suicide or survival. The critical factor was the connection to a second protein called ATM – a sort of “boss” molecule that oversees the actions of BID and a number of other proteins. The team discovered that when ATM interacts with BID, the cell stays alive. When ATM refrains from this interaction, BID attaches to proteins on the surface of organelles called mitochondria – the cell’s power plants – to initiate the series of events leading to cell death.
In research that appeared recently
in Nature Cell Biology
, Gross and his team set out to get a better picture of BID activity. Together with research students Maria Maryanovich and Galia Oberkovitz, and postdoctoral fellow Dr. Hagit Niv, he created and characterized mice in which the BID protein was mutated: It was unable to accept orders from ATM. After damaging the mice’s DNA, the team watched to see what would happen.
In studies led by Maryanovich, they found that BID is a regular multi-tasker. On the one hand, it does, as they had seen in the lab dishes, administer the cell’s decision to either commit suicide or keep things on hold while repairs are carried out. Unsurprisingly, the team found that cells with the mutated BID had a high suicide rate, especially in the bone marrow, which is highly sensitive to DNA damage. On the other hand, in a seemingly unrelated act, BID also directs the conversion of stem cells that reside in the bone marrow into functional blood cells. These blood stem cells, a kind of adult stem cell, are used to replace all types of blood cells over an organism’s lifetime, and their differentiation is a tightly controlled process. But when BID couldn’t communicate with ATM, the mice’s blood stem cells differentiated without restraint, soon depleting the supply.
To understand how BID does two jobs at once – directing both suicide and stem cell differentiation – the scientists had to find out where it was going and which proteins it was hooking up with. The cell nucleus, for instance, was where they found the meetings with ATM taking place. The experiments suggested that ATM brings along a physical restraining order telling the BID protein to stay where it is. Without ATM's restraining stamp, BID is free to wander off to its alternate site – the mitochondria – where it meets its other contact on the mitochondria’s outer surface. This is where things start to happen: The interaction spurs the creation of reactive oxygen species – the cells’ all-purpose stress molecules. The reactive oxygen species are like buckshot, tearing holes in the mitochondrion wall to release cell-killing toxins. But these molecules also work as SOS signals to the stem cells, calling on them to differentiate in a hurry.
The scientists think that the ATM-BID partnership is a sort of control mechanism that senses the amount of DNA damage in a cell and adjusts reactive oxygen species levels accordingly. The findings, says Gross, are surprising – not just for the new function they have revealed for BID. They have yielded interesting insights into previously unsuspected connections between the mitochondria and the cell nucleus, as well as revealing tight coordination between two parts of the cellular life cycle – cell suicide and adult cell replenishment.
Gross and his team believe that these findings and insights may, in the future, have biomedical relevance. ATM mutations in humans cause a rare but devastating degenerative disease that appears in childhood and affects all parts of the body. Many of the worst effects seem to be tied to excess reactive oxygen species, and Gross thinks that finding ways to block BID could relieve symptoms and extend life. But there may be much broader applications: Recent research hints that the behavior of BID and the other proteins it interacts with may be linked to such metabolic syndromes as obesity and diabetes, as well as autoimmune diseases and even cancer. So it might be helpful to find ways of directing BID proteins to the right place and the proper meetings, at the right time.
Also participating in this research were Dr. Yehudit Zaltsman and Lidiya Vorobiyov of the Biological Regulation Department, Profs. Steffen Jung and Tsvee Lapidot of the Immunology Department, and Drs. Rebecca Haffner and Ori Brenner of the Veterinary Resources Department.
Prof. Atan Gross’s research is supported by the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Pearl Welinsky Merlo Foundation; the Helen and Martin Kimmel Institute for Stem Cell Research; the Clore Center for Biological Physics; the Yeda-Sela Center for Basic Research; and the Dr. Josef Cohn Minerva Center for Biomembrane Research.