“Make sure to keep your immune system healthy!” How many times have you heard your doctor tell you take care of your immune system? Perhaps when you think about your immune system you picture T-cells and B-cells actively gorging themselves on disease-causing microorganisms and viruses in your body. This picture, although mostly correct, only represents the active immune system. The active immune system is the facet of the overall immune system that utilizes T-cells and B-cells to recognize, “remember”, and destroy invading pathogens.
The other facet of the immune system that is often glossed over is the innate immune system. The innate immune system is the first line of defense against invading pathogens in the human body; it consists of cells, receptors, signaling cascades, and inflammatory responses that defend the body against invaders and recruit the active immune system to the site of the infection. Much is unknown about the underlying molecular mechanisms that dictate the workings of the innate immune system. Yet we do know that they have a wide array of functions; from immune function to aging to longevity.
Yet we do know that they have a wide array of functions; from immune function to aging to longevity.
THE INNATE IMMUNE SYSTEM: RNASE L AND IREI – PARTNERS IN CRIME
Innate immune system research is at the interface between basic science and healthcare; understanding the pathways implicated in this system will lead to better disease models, early diagnostic tools, and possibly even disease treatments. Here at Princeton University, Professor Alexei Korennykh is working on elucidating the basic signaling pathways of RNase L and Ire1, two proteins in the innate immune system that exhibit highly unusual behavior. These two proteins are kinases, or enzymes that modify other proteins by adding phosphate groups to them; kinases are mostly implicated in transducing signals in cellular pathways. They are part of the overall human kinome, which consists of all the protein kinases in an organism’s genome. RNaseL and Ire1 are widespread in the human body, but unlike the rest of the human protein kinome, these kinases do not use phosphorylation as a main signaling mechanism. Their signaling pathways and mechanisms of action are still not completely understood, but it is clear that they are unique and important in their function and structure. RNaseL has a main role in the destruction of all the viral and cellular RNA within in a cell, which is part of a cell’s “last stand” before destroying itself in response to a viral infection (this “suicide” process is called apoptosis).
RNASE L: THE CELL’S LAST STAND
RNase L has evolved from Ire1, which is a classic receptor of the unfolded protein response. The unfolded protein response (UPR) is a cellular stress response that originates in the Endoplasmic Reticulum (ER) of a cell. When misfolded proteins are found in the ER, the UPR is activated and an attempt is made to fix the problem. If the problem is found to be irresolvable, the cell undergoes apoptosis. Although the separate pathways of these two receptors don’t entirely relate at this time, the Korennykh lab hopes to explore the possible connections between these two anomalous kinases. For now, Dr. Korennykh is focusing on the RNase L pathway in the cell.
WE CAN LIVE LONGER… BUT SUFFER INFLAMMATION?
RNase L is a classic receptor in the inflammatory response and has been shown to be very important in longevity; RNase L knockout mice, which lack this receptor, live 30% longer than wild-type mice, but also suffer from heavily inflammation. This result is paradoxical, for although the mice live longer, they suffer more from inflammation. This varied response attests to the involvement of this pathway not only in antiviral defense, as exhibited by the heavy inflammation, but also in the normal cell cycle, as attested to by the longevity of the mice. Since RNase L is present in all cells, and seems to have an interesting function in the cell, it has the potential to be targeted for therapeutic use. But in order to manipulate or use the RNase L pathway in a medically beneficial way one must first elucidate the inner working of the pathway itself.
THE RNASE L PATHWAY
Korennykh’s lab is currently working on dissecting the RNase L pathway, finding its key proteins, and fully understanding its underlying mechanisms. Although the lab uses computational modeling to rule out prospective hypotheses concerning protein interactions, they focus mostly on actual experimental work. They use time-dependent experiments to study the events of the signaling cascade and x-ray diffraction and other structural biology methods to study the key proteins in the pathway. Dr. Korennykh says, “I really believe in experiment. We always want to some crystal, or high-resolution structure, of the receptors of the unknown receptor…the fastest way to get the structure is to crystalize the protein and solve it. We really believe in the experimental approach to structural biology; computational methods, for us, is mostly useful is ruling out certain hypothesis.” The Korennykh lab has elucidated many structures in the RNaseL and Ire1 pathways as of late. Identifying the key proteins of the pathway is the first step to fully understanding the full mechanisms behind these pathways.
FUTURE: SIMPLE BLOOD TEST FOR ALZHEIMER’S?
This is just the beginning; elucidation of a pathway and its mechanisms is the first step to eventual medical applications. But, solving the crystal structures of certain key molecules can definitely provide an application of their own. Dr. Korennykh hopes that some of the structures that his lab has already found, structures that are reporters for inflammation, will be used in the diagnosis of inflammatory diseases. The logic is to test human samples for the presence of these early indicators of inflammation, which would in turn help to identify inflammatory diseases early in their onset. Eventually the lab hopes to find applications of their research in the early detection and treatment of neurodegenerative diseases, like Alzheimer’s, which display high levels of inflammation. Maybe soon we will have simple blood tests for the early diagnosis of Alzheimers and other diseases characterized by inflammation.