For some pathogens, attack is the best form of defense – they enter immune cells of the human body. However, if they are detected in their hidden niche, the infected cell kills itself to re-expose the pathogens. In the “EMBO Journal” a research group at the University of Basel’s Biozentrum has reported that a protein called gasdermin forms permeable pores in the cell membrane and thus triggers the suicide of the immune cell.
The best hiding place often lies behind enemy lines, as many bacteria such as the pathogens responsible for tuberculosis or typhoid have realized. They invade immune cells and can survive there, well hidden, for some time. To eliminate such invaders, the host macrophages can initiate a suicide program.
Mechanism of pore formation by the protein gasdermin D, resulting in cell death.
University of Basel, Biozentrum
Together with researchers at the Novartis Institute for Biomedical Research and ETH Zurich, the team led by Prof. Sebastian Hiller from the Biozentrum at the University of Basel has shown for the first time that a “death protein” perforates the cell membrane, resulting in macrophage bursting open. The re-exposed pathogens can then again be fought by the immune system.
Gasdermin D: Executioner in the cell
Tiny cell components of invading pathogens are recognized by receptors inside macrophages. These, in turn, activate a signaling cascade, which triggers an inflammatory response and initiates pyroptosis – a specific form of programmed cell death.
“Some studies have already demonstrated that the protein gasdermin D plays a central role in pyroptosis,” explains Prof. Petr Broz, one of the main authors of the study. “We have now discovered how gasdermin drives immune cells to suicide and using cryo-electron and atomic force microscopy we could visualize the pores in the cell membrane.”
The protein gasdermin D is at the end of a long signaling pathway. Intracellular receptors recognizing foreign bacterial components induce the assembly of the inflammasome. This protein complex, in turn, activates enzymes that generate active gasdermin fragments by proteolytic cleavage.
“In the macrophages, gasdermin D is the executioner, which carries out the death sentence,” says Hiller, clarifying the role of the protein. “The cleaved gasdermin D fragments rapidly target the cell membrane of macrophages and permeabilize it by forming a pore. The porous membrane leads to cell swelling and bursting.”
Gasdermins cooperate in cell suicide
With gasdermin D, the researchers have not only identified the protein that deals a deathblow to immune cells, but they could also visualize pore formation using high-resolution microscopy techniques. As it turns out, following the cleavage of gasdermin D only one of the two fragments is required for the seamless integration into the cell membrane.
So far, only little is known about the gasdermin family of proteins, which along with gasdermin D includes five other members. In the future, Hiller’s team aims to investigate the structure and function of several gasdermins to determine whether and how they cooperate in pore formation and to identify the physiological context in which these proteins induce pyroptotic cell death.
Lorenzo Sborgi, Sebastian Rühl, Estefania Mulvihill, Joka Pipercevic, Rosalie Heilig, Henning Stahlberg, Christopher J. Farady, Daniel J. Müller, Petr Broz and Sebastian Hiller
GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death
EMBO Journal; published online 14 July 2016, doi: 10.15252/embj.201694696
Prof. Sebastian Hiller, University of Basel, Biozentrum, tel. +41 61 267 20 82, email: email@example.com
Dr. Katrin Bühler, University of Basel, Communications Biozentrum, Tel. +41 61 267 09 74, email: firstname.lastname@example.org
Heike Sacher | Universität Basel
Molecular Force Sensors
20.09.2017 | Max-Planck-Institut für Biochemie
Foster tadpoles trigger parental instinct in poison frogs
20.09.2017 | Veterinärmedizinische Universität Wien
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...
Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
20.09.2017 | Life Sciences
20.09.2017 | Power and Electrical Engineering
20.09.2017 | Physics and Astronomy