Analysis of sperm differentiation reveals new mode of proteasome regulation

Early in development, cells undergo a controlled demolition that helps to shape their raw, pliable material into the specialized forms they must have to do their jobs as adults. The process by which this occurs is also crucial later in the cell’s life, to take out potentially dangerous trash that routinely accumulates as it ages. New work from Rockefeller University has now provided a detailed genetic and biochemical understanding of how one protein helps modulate this sculptor and janitor of the cell, known as the proteasome. The findings improve our knowledge of how cells specialize, and could also lead to new tools for fighting cancer and degenerative disorders.

A good place to study the proteasome in action is in the developing sperm cell, which prunes away much of its cell mass to cut a sleek and efficient swimmer. “It’s got to be a light, efficient DNA delivery vehicle,” says Hermann Steller, head of the Strang Laboratory of Apoptosis and Cancer Biology. Through a genetic screen of sterile, male flies, the team isolated a protein, called Nutcracker, without which sperm cell remodeling does not occur, causing sterility. Nutcracker is part of the larger SCF complex, which helps regulate the destruction of proteins involved in cell cycle control, among other things.

Maya Bader, a former doctoral student in Steller’s lab, undertook the arduous dissection of 10,000 fruit fly testes to screen for proteins that were interacting with Nutcracker. Using mass spectrometry, she identified DmPI31, a molecule originally described as an inhibitor of proteasome activity in mammalian cells about 10 years ago. But the researchers were in for a surprise: probing the function of DmPI31 with genetic and biochemical experiments, they found that it did not inhibit but rather enhanced proteasome activity, and that its absence was lethal, according to experiments to be published April 29 in Cell.

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