Natural Killer (NK) cells, a component of our innate immune system, are a type of lymphocyte designed to play a major role in defending our bodies in the host-rejection of both virally infected cells and cancer cells, thus protecting our bodies from harm.
Now, for the first time, scientists at Vetmeduni, the University of Veterinary Medicine, Vienna, Austria, show that NK-cell activity can be influenced by phosphorylating STAT1, a protein in NK cells. The results, which could be of immediate therapeutic relevance, are published in the August 8, 2013 edition of Cell Reports.[1]
Stopping CDK8 from inactivating STAT1 in NK-cells stimulates tumor surveillance and may lead to a new treatment option against malignant cells.
STAT1
Since its discovery in the early 1990s, the protein STAT1 (Signal Transducer and Activator of Transcription 1), is involved in upregulating genes due to a signal by either type I or type II interferons, and, as a results, are central in passing signals across immune cells, ensuring that our bodies react quickly and appropriately to threats from viruses or other pathogens. Animals without STAT1 are also prone to develop cancer, suggesting that STAT1 is somehow involved in protection against malignant cells.
The STAT1 protein is known to be phosphorylated on at least two positions: phosphorylation of a particular tyrosine (tyr-701) is required for the protein to enter the cell nucleus (where it exerts its effects), while subsequent phosphorylation of a serine residue alters the way it interacts with other proteins, thereby affecting its function.
First responders
Natural Killer (NK) cells are among the first cells to respond to infections by viruses or to attack malignant cells when tumors develop. When they detect cells to be targeted, they produce a number of proteins, such as granzyme B and perforin.
When released in close proximity to a cell slated to be killed, perforin forms pores in the cell membrane of the infected target cell through which the granzymes and associated molecules can enter, inducing apoptosis – destroying them from within. This lethal activity must be tightly controlled to prevent NK-cells from running wild and destroying healthy cells or tissues. But how is this done?
Mutation
Eva Maria Putz and colleagues at the Institute of Pharmacology and Toxicology of the University of Veterinary Medicine, Vienna have investigated the importance of STAT1 phosphorylation in NK-cells. The researchers found that when a particular serine residue (ser-727) in the STAT1 protein is mutated, NK-cells produce far higher amounts of granzyme B and perforin and are far more effective at killing a wide range of tumor cells. Mice with the correspondingly mutated Stat1 gene are far less likely to develop melanoma, leukemia or metastasizing breast cancer. On the other hand, when the same serine residue is phosphorylated, the NK-cells are less able to kill infected or cancerous cells.
The researchers have accumulated a large body of evidence to suggest that the cyclin-dependent kinase CDK8 phosphorylates STAT1 on serine 727. Surprisingly, this phosphorylation does not require prior phosphorylation of the activating tyrosine residue in NK-cells. Instead, the researchers found that this seems to represent a way in which the lethal activity of the NK-cells is kept in check.
Commenting on the finding, Putz points to the potential significance of the finding. ?If we can stop CDK8 from inactivating STAT1 in NK-cells, we could stimulate tumor surveillance and thus possibly have a new handle on treating cancer, harnessing the body?s own weapons against malignant cells.?
Illustration: Inhibition of NK cells by phosphorylation of STAT1-Serin 727 mediated by CDK8. Courtesy: Eva-Maria Putz/Vetmeduni, Vienna, Austria. [See full description]
Featured Image: Cancer cell. Courtesy: ? 2013 Fotolia. Used with permission.
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