Display of “Eat-Me” Signal on Cell Surfaces of Unwanted Cells Requires Activation of a Lipid-Scrambling Protein by a Nuclear Protein Fragment

Scientists at the Institute for Integrated Cell-Material Sciences (iCeMS) (Kyoto University) and colleagues in Japan have revealed molecular mechanisms involved in eliminating unwanted cells in the body. A nuclear protein fragment released into the cytoplasm activates a plasma membrane protein to display a lipid on the cell surface, signaling other cells to get rid of it (see small image at left and enlarged image below). The findings were published online on March 15, 2021 in journal Molecular Cell. The article is titled “Caspase cleavage releases a nuclear protein fragment that stimulates phospholipid scrambling at the plasma membrane” (https://www.cell.com/molecular-cell/fulltext/S1097-2765(21)00135-0). "Every day, ten billion cells die and are engulfed by blood cells called phagocytes. If this didn't happen, dead cells would burst, triggering an auto-immune reaction," explains iCeMS biochemist Jun Suzuki, PhD, Professor, Deputy Director of Medical Biochemistry and Cell Membrane Biology, who led the study. "It is important to understand how dead cells are eliminated as part of our body's maintenance." Scientists already know that dead cells display an “eat me” signal on their surface that is recognized by phagocytes. During this process, lipids are flipped between the inner and outer parts of the cell membrane via a variety of proteins called scramblases. Dr. Suzuki and his team have already identified several of these lipid-scrambling proteins, but some of their activation mechanisms have been unclear. To solve this, the team used an array of screening approaches to study the scrambling protein called Xkr4. The broad aim was to single out the genes that are active during cell death and to specifically zoom in on Xkr4 and its associated proteins to understand how they interact.
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