Enzyme Found to Trigger the Immune System, Providing Clues on Alzheimer’s-Related Protein

In its newly discovered role, SPPL3 has been found to function without chopping proteins to activate T cells, the immune system’s combat forces. Because its structure is similar to that of presenilin enzymes, which have been implicated in Alzheimer’s Disease (AD), the researchers hope their new findings will provide better treatment options for the debilitating disorder.

A summary of their findings was published on December 22, 2014, in the journal Molecular and Cellular Biology. “No one could have predicted that SSPL3 was involved in T cell activation,” stated Joel Pomerantz, PhD, an associate professor of biological chemistry at Johns Hopkins University (JHU; Baltimore, MD, USA). “It walks like a duck and quacks like a duck, but its duck-like abilities don’t come into play here.”

T cells are immune system cells that destroy invading cells and help activate other immune cells. When a foreign protein binds to a receptor protein on the outside of a T cell, a signal relay system is activated. It finishes when a protein called NFAT (nuclear factor of activated T cells) moves to the nucleus and triggers a number of genes to effectively prepare the T cell for battle. Some of what happens in between is known, however, Dr. Pomerantz and his colleagues wanted to find more players in the process.

The researchers searched for proteins that could increase NFAT’s activity and found SPPL3, an enzyme that proved essential to NFAT’s activation but had never before been implicated in immune system function. Additional testing accurately placed SPPL3 within the sequence of events that lead to NFAT activation.

SPPL3 lives in the membrane of the endoplasmic reticulum (ER), a ruffled, membrane-bound compartment inside the cell that helps process new proteins, where it seems to encourage interactions between STIM1 and Orai1, two known components of the NFAT signal relay system. However, SPPL3 was found to accomplish this without using its enzymatic, or protein-cutting, abilities. It also encourages the release of calcium from the ER, which contributes to the signaling system though it is unclear whether this is something it does directly or indirectly. “SPPL3 is a relatively uncharacterized protein that had never before been implicated in immune system function,” said Dr. Pomerantz. “It opens up a whole new set of scientific questions.”

Dr. Pomerantz believes that SPPL3 could be used as a drug target to either augment the activation of T cells in immunodeficient individuals or to suppress it in those with overactive immune systems. He also plans to study the ability of SPPL3 to mediate the influx of calcium into the cell and the release of calcium from the ER, since calcium is key to the functioning of many cell signaling networks.

Related Links:
Johns Hopkins University