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!
Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg
Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH
A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.
By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...
Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
23.02.2018 | Life Sciences
23.02.2018 | Earth Sciences
23.02.2018 | Materials Sciences