A Protein Complex Restrains a Homicidal Enzyme during Sperm Differentiation

If one were to take a moral view of cell activities, the caspases would be condemned on two counts. They not only give the order to kill cells, they also carry it out. But in the real-life utilitarian world of the cell, all this killing is simply a means to an end. Programmed cell death, or apoptosis, plays an important role in embryonic development and in protecting the body from damaged or aged cells. Caspases can also function without killing cells—for example, during infl ammation, cellular differentiation, and morphogenesis—but even these nonlethal processes usually require the destruction of unwanted components. In the fruit fl y Drosophila , for example, caspases facilitate the radical remodeling that liberates individual sperm from a cytoplasm-fi lled cyst containing 64 interconnected spermatids. During this process, called spermatid individualization, the cyst dispatches most of its cytoplasm and organelles into " waste bags " to yield the sleek DNA-delivery machines we call sperm. What restrains the lethal machinations of caspases to allow selective degradation of subcellular components is not clear, though there is evidence that inhibitory proteins (called inhibitor of apoptosis proteins, or IAPs) may prevent caspase activation at inappropriate times. In a new study, Eli Arama et al. provide support for this scenario by showing that an enzyme complex activates caspases by degrading their inhibitors during Drosophila sperm differentiation. Although the complex has been linked to protein degradation before, its role in caspase regulation came as a surprise. Almost every multicellular organism harbors caspase precursors that remain nearly dormant until aptly named activator proteins convert them into " initiator " complexes, which in turn activate " effector " caspases—the executioner enzymes. Once activated, effector caspases shear off protein fragments from a number of cellular targets, compromising their function and leading to apoptosis. IAPs can block caspase activity, and thus cell death, in insects and mammals. The Drosophila IAP (called Diap1) thwarts apoptosis by degrading an initiator caspase; Diap1 is inactive, however, in cells destined to die. Diap1 encodes an enzyme (E3 ubiquitin ligase) that marks proteins for destruction by modifying them with small molecules called ubiquitin. To determine which molecules rein in caspases' lethal tendencies during sperm differentiation, the researchers analyzed a collection of over 1,000 lines of sterile mutants with defects in spermatid individualization. By isolating numerous strains with the same defect and crossing them in various combinations, researchers can identify " complementation groups " …