Controlling cell acidity could be key to autoimmune disease

PHILADELPHIA— 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,” Miner said.  

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.

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System (UPHS) and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.

The Perelman School of Medicine is consistently among the nation's top recipients of funding from the National Institutes of Health, with $580 million awarded in the 2023 fiscal year. Home to a proud history of “firsts,” Penn Medicine teams have pioneered discoveries that have shaped modern medicine, including CAR T cell therapy for cancer and the Nobel Prize-winning mRNA technology used in COVID-19 vaccines.

The University of Pennsylvania Health System cares for patients in facilities and their homes stretching from the Susquehanna River in Pennsylvania to the New Jersey shore. UPHS facilities include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Lancaster General Health, Princeton Health, and Pennsylvania Hospital—the nation’s first hospital, chartered in 1751. Additional facilities and enterprises include Penn Medicine at Home, GSPP Rehabilitation, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is an $11.9 billion enterprise powered by nearly 49,000 talented faculty and staff.