Head tucked, arms and legs stretched straight – a swimmer has now assumed a streamlined position. Sperm, those consummate swimmers, go to far more extreme lengths to achieve their streamlined shape – they commit a form of near suicide.
Cell suicide – apoptosis – is a natural process that occurs in many tissues, eliminating aged, damaged or potentially harmful cells. The agents of the final execution are proteins called caspases, and it was thought that once caspases are activated, the cell is condemned to certain death. But together with colleagues at Rockefeller University, USA, while conducting postdoctoral research there, Dr. Eli Arama, now at the Institute’s Molecular Genetics Department, showed that a fruit fly sperm harnesses this cellular suicide mechanism to streamline its physique near the end of its development. Any excess baggage not absolutely necessary for getting the sperm and its load of DNA upstream to the egg gets collected and deposited into a sort of waste bag, where it is then degraded by the caspases. This process, called sperm individualization, results in a sleek individual sperm, primed to swim for its life. When this apoptosis-like program, and thus sperm individualization, goes awry, males become sterile.
How exactly do sperm evade the zeal of the executioner proteins, keeping them activated in the right place and at the right time, without them actually driving the sperm to suicide? In normal cells, caspase activity is restrained by protein inhibitors, which act as the system’s brakes. When the green light is given for cell suicide, the inhibitors get degraded – releasing the brakes and allowing the caspases to commence the suicide ritual.
Arama and his colleagues have now uncovered a new pathway for regulating caspases during sperm development. Their findings have recently been published in PLoS Biology. The researchers screened over 1,000 sterile male fruit flies for mutations that block caspase activation. They eventually identified 22 distinct genes that are required for caspase activation; the protein products of two of them form a “brake-release” complex. One of the proteins that make up the complex is called Cullin-3, a member of a family of proteins well known for its role in marking proteins with a molecular tag – ubiquitin – consigning them to destruction. It turns out that the Cullin-3 complex adds ubiquitin tags to the caspase inhibitors at the beginning of sperm individualization, releasing the brakes on the executioner proteins. This is the first time that cullins have been linked to caspase regulation. If any of the proteins in the complex contain mutations, streamlined sperm don’t form, and the males are sterile.
Although the research took place in fruit flies, Arama points out that their sperm individualization process is very similar to that of humans and may have important implications for research into male infertility. In addition, faulty apoptosis is involved in many diseases and conditions, and Arama’s findings may lead to new insights into the general mechanisms underlying cell suicide.
Dr. Eli Arama’s research is supported by the M.D. Moross Institute for Cancer Research; the Nella and Leon Benoziyo Center for Neurological Diseases; the Chais Family Fellows Program for New Scientists; the Samuel M. Soref and Helene K. Soref Foundation; the Henry S. and Anne S. Reich Research Fund for Mental Health; and Lord Mitchell, UK.