New research from scientists at the Howard Hughes Medical Institute and Rockefeller University has now uncovered a new pathway that regulates these killer proteins, yielding new knowledge about caspase function as well as insights into the causes of human infertility. The findings are reported in the
Cell death caspases, when activated, were thought to condemn a cell to certain death. But a few years ago Hermann Steller, head of the Laboratory of Cancer and Apoptosis Biology, and his colleagues discovered that caspases also function without entirely killing cells; instead, they are used to shape cells by dismantling unwanted bulk. “This process is very similar to apoptosis, or cell suicide,” explains Steller, who is Strang Professor at Rockefeller and an investigator at HHMI, “but in this case cells live.” And in Drosophila, when this cell death-like program goes awry, males become sterile.
Though quite a bit has been learned about how caspases are activated, very little is known about how unwanted caspase activity is restricted so that healthy, productive cells aren’t mistakenly target for death. So Steller and his colleagues wanted to figure out how caspases, which are expressed in all cells, are activated at the right time and at the right place; and in this case, how they do not kill off a cell entirely.
The researchers screened more than 1,000 sterile male fruitflies, looking for cellular differences between sterile flies and fertile ones. They then mapped these differences back to the genes to identify mutations along the Drosophila genome that made these fruitflies sterile. This process eventually pointed them to three distinct genes that encode different protein components of a complex called Cullin-3 ubiquitin ligase.
Cullins are members of the E3 ubiquitin ligase family, which label other proteins with ubiquitin, a molecule that marks them for degradation. It turns out that Cullin-3, in conjunction with two other proteins, activates caspases by degrading a caspase inhibitor. This, in turn, initiates a cell death-like program at the right time and at the right place — in the developing testes of Drosophila — and gets rid of unwanted cytoplasm and organelles. Before this study, only IAPs, another class of E3 ubiquitin ligases, had been identified as caspase regulators. Now, Steller and his group have found a new major player that regulates these killer proteins.
One of the proteins that form the Cullin-based complex in Drosophila has also been linked to male infertility in mice and humans. In mice, a mutation in the gene that encodes a protein called Klh110 causes male sterility. In humans, male infertility has been linked to this gene as well, although it is still not known whether this is due to the inability of Cullins to activate caspases and promote sperm differentiation.
The Steller lab initially focused on the role of Cullins during sperm development, but there is already data indicating that they also function to regulate caspases in somatic cells. It appears that cells use several different mechanisms simultaneously to protect themselves against unwanted caspase activity and death. This information provides new opportunities to develop drugs that can alter cell death for therapeutic purposes, either for cellular protection or cell killing — processes that range from neurodegenerative disease to cancer.
“Our findings provide a new framework to understand how apoptotic proteins are regulated for cellular remodeling.” says Steller. “And now, by having a more comprehensive picture of these different pathways and how they come together, we are prepared to look much more broadly at different cell death paradigms.”
Thania Benios | EurekAlert!
Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory
Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP
Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.
Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
09.12.2016 | Life Sciences
09.12.2016 | Ecology, The Environment and Conservation
09.12.2016 | Health and Medicine