Septin important in T cell calcium channel activation and T cell survival and activation - new study
Researchers report that a certain type of protein called septins play a critical role in activating a calcium channel on the surface of the T cell. The channel is the membrane door through which calcium enters T cells, an action essential for the T cell's survival, activation, and ability to fight disease.
T cells are specialized white blood cells that are important in fighting infection. These cells have the ability to directly kill infected cells or help in immune response against infection.
Septins have been reported to be important in building 'cages' around bacterial pathogens, immobilizing the harmful microbes and preventing them from invading other healthy cells.
The authors used a genome-wide RNA interference screen in HeLa cells to identify filamentous septin proteins as crucial regulators of store-operated Ca2+ entry. According to the report septin rearrangement at endoplasmic reticulum-plasma membrane junctions is required for some critical cell signaling. According to the authors, their data show that septins organize the highly localized plasma membrane domains that are important in a certain critical signaling pathway, and indicate that septins may organize membrane microdomains relevant to other signaling processes.
The authors describe the discovery as another important step in understanding the overall functioning of T cells – knowledge from which new, more precisely targeted drugs to treat diseases ranging from cancer to viral infections can emerge. "It's like working on an engine, you have to know what all the parts are doing to repair it," he says. "We want to understand the basic machinery inside a T cell. This will enable us to target the specific pressure points to turn up a T cell response against a tumor or virus or to turn it down in the case of autoimmune diseases."
The findings were published in the journal Nature.
"We have found that the septin protein is a very strong regulator of the calcium response, which is essential for activating immune cells," says Dr. Sharma, who leads her own independent laboratory at the La Jolla Institute.
Dr. Hogan says the discovery took the research team by surprise. "We knew septins existed in the cellular plasma (surface) membrane, but we didn't know they had anything to do with calcium signaling," he says. Septins are known to build scaffolding to provide structural support during cell division.
To the research team's surprise, the septins were forming a ring around the calcium channel. "We aren't sure why, but we theorize that the septins are rearranging the cellular membrane's structure to "corral" the key proteins STIM and ORAI1, and maybe other factors needed for the calcium channel to operate," says Dr. Hogan.
Dr. Sharma adds that, "essentially we believe the septins are choreographing the interaction of these two proteins that are important in instigating the immune response." Without the septins' involvement, T cell activation does not occur.
In the study, the researchers devised a simple visual readout of activity in a main pathway responsible for activation of T cells— the same pathway that is targeted by the immunosuppressive drug cyclosporin A that is used clinically — and looked for impairment of the activity when individual genes were, in effect, deleted. After sorting through the roughly 20,000 human genes, they turned up 887 gene "hits," says Dr. Hogan.
With further experiments, they should be able to classify those hits into genes that affect the calcium channel itself and genes that act later in the pathway. "We are hopeful that one or more of these genes can be used as a clinical target for new drugs to treat transplant rejection and immune diseases, some of the same indications now treated with cyclosporine A," adds Dr. Hogan. He believes that a medication aimed at an early step of calcium entry through the ORAI channel could be more effective and have fewer side effects than cyclosporin A, which targets a later step in the pathway and can cause complications such as kidney disease.
An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry.Nature June 23, 2013. doi: 10.1038/nature12229.
Amanda Mascarelli. Septin proteins take bacterial prisoners. A cellular defence against microbial pathogens holds therapeutic potential. Nature 05 December 2011