When killer T cells of the immune system encounter virus-infected or cancer cells, they unload a lethal mix of toxic proteins that trigger the target cells to self-destruct. A new study shows T cells can initiate cellular suicide, also known as programmed cell death or apoptosis, by a previously unrecognized pathway that starts with the destruction of a key enzyme in mitochondria, the power plant of the cell.
The study, from the lab of Judy Lieberman, a senior investigator at the Immune Disease Institute and Professor of Pediatrics at Harvard Medical School, reveals that T cells use both the novel pathway and the classical apoptotic pathway to interfere with mitochondrial function and induce cell death.
“This work gives us a new understanding of a major T cell defense pathway,” Lieberman says. The results will appear in the May 16 issue of Cell.
The Lieberman lab studies cytotoxic T lymphocytes (CTLs), key cells in the immune defense against viral infection and cancer. When CTLs recognize an infected or transformed target cell, they release the contents of cytolytic granules onto the target cell. These granules contain serine proteases called Granzymes, which induce programmed cell death in the target cells. Two major Granzymes, A and B, account for most of the killing activity in granules.
Granzyme B triggers the classical programmed cell death pathway involving breakdown of the outer mitochondrial membrane, and the release of death-promoting proteins which activate the caspase protease cascade and result in massive DNA damage.
Previous work from the Liebeman lab showed that Granzyme A initiates cell death by a different biochemical pathway. That pathway involves the mitochondria, but does not result in mitochondrial membrane breakdown or caspase activation, and triggers a different type of DNA damage. The current study was aimed at understanding how Granzyme A kills cells.
To identify Granzyme A target proteins in mitochondria, Lieberman and colleagues used proteomics to look at the fate of a large number of mitochondrial proteins after Granzyme A exposure. One protein, NDUFS3, a subunit of the large multi-protein Complex I assembly that participates in energy generation for the cell, disappeared.
Further work established that when Granzyme A was released into a cell, it could enter the mitochondria where it degraded NDUFS3. Further, the investigators showed that loss of NDUFS3 caused mitochondria to produce damaging reactive oxygen, known to be essential for Granzyme A’s deadly effects on cells. Destruction of NDUFS3 was sufficient to initiate the toxic effects of Granzyme A on human cells, they showed.
The new demonstrate that while both Granzymes target mitochondria, they do so in very different ways. Lieberman says she is not surprised that immune cells have multiple means of inducing mitochondrial-dependent cell death. “Many viruses and cancers have found ways to be resistant to the caspase-dependent apoptosis pathway triggered by Granzyme B, so it makes sense that immune cells would have a second, parallel pathway to cause cell death,” she said.
Written by Pat McCaffrey
The lead author on the paper is Denis Martinvalet, a postdoctoral fellow in the Lieberman lab. Other authors include Derek M Dykxhoorn, and Roger Ferrini of the Immune Disease Institute.
David Cameron | Harvard Medical School
When Air is in Short Supply - Shedding light on plant stress reactions when oxygen runs short
23.03.2017 | Institut für Pflanzenbiochemie
WPI team grows heart tissue on spinach leaves
23.03.2017 | Worcester Polytechnic Institute
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
23.03.2017 | Life Sciences
23.03.2017 | Power and Electrical Engineering
23.03.2017 | Earth Sciences