Regulating cell acidity could transform autoimmune disease treatments

What if treating autoimmune diseases was as simple as regulating the acidity levels of parts of patients' cells? Genetic screening may have unlocked a path for treating the severe inflammation associated with many immune diseases by regulating one protein's role in helping another protein control cell acidity, according to new research published in Cell by a team from the Perelman School of Medicine at the University of Pennsylvania. 

A protein called STING is one of the key triggers of inflammation in the body, and when it malfunctions, such as via a genetic mutation, it can cause conditions where severe inflammation occurs. One of these autoimmune conditions is the ultra-rare STING-associated vasculopathy with onset in infancy (SAVI). It begins in childhood due to mutated STING proteins, and causes debilitating inflammation in the skin, lungs, and other vital organs. More than 50 people have been diagnosed with SAVI since 1980, and there are few treatment options for it. Many patients die within their first 20 years of life. 

Another of STING's main functions is regulating the acidity within the Golgi apparatus, a structure within cells that processes, packages, and transports proteins and lipids in the body. One type of protein that the Golgi apparatus transports is the cytokine, which is important to the growth and activity of the immune system. Fluctuations in the acidity level of the Golgi apparatus can influence that transportation system, in turn impacting cytokines and thus, the immune system. 

A "helper protein" is crucial

"We already knew STING regulated Golgi apparatus acidity. This happens by means of proton channel activity, a system by which hydrogen atoms can move through cell membranes. But the exact way STING controlled acidity wasn't totally clear," said senior author Jonathan Miner, MD, PhD, an associate professor of Rheumatology and Microbiology and a member of Penn's Colton Center for Autoimmunity. "When we screened the entire genome of a patient with SAVI, we were led to a protein that directly affected STING called ArfGAP2."

Along with co-senior author David Kast, PhD, a former post-doctoral fellow at Penn Medicine who is now an assistant professor of Cell Biology and Physiology at Washington University in St. Louis, Miner and the team discovered that a "helper" protein, ArfGAP2, was found to be crucial by affecting the ability of STING and its proton channel activity to regulate acidity in the Golgi apparatus. 

With ArfGAP2's role identified, the researchers explored its therapeutic potential via their small animal models of SAVI. When they genetically deleted ArfGAP2, there was a significant drop in STING activity that corresponded with strong reductions in inflammation and autoimmune activity. 

It is remarkable that something as small as the acidity of a tiny organelle within a cell could make such a big difference."

Jonathan Miner, MD, PhD, Associate Professor of Rheumatology and Microbiology and member of Penn's Colton Center for Autoimmunity

Therapeutic potential for hundreds of autoimmune diseases

Beyond SAVI, STING is involved in hundreds of diseases, including some forms of lupus and retinal vasculopathy with cerebral leukoencephalopathy (RVCL)-one of Miner's main focus areas in research and clinical practice. 

"Our exploration not only illuminates the genetic foundations of autoimmunity but also opens up new avenues for transformative treatments aimed at improving the lives of millions," Miner said. 

Moving forward, the researchers hope to develop therapies that could be instituted clinically to disrupt ArfGAP2, such as through small molecule medicines that could be taken as simply as by swallowing a pill. 

This research was supported by two grants from the National Institutes of Health (R01 NS131480 and R01 AI143982). It also received support from the Clayco Foundation.