Caption: Jay Xiaojun Tan, assistant professor of cell biology, School of Medicine, and member of the Aging Institute, University of Pittsburgh, is an author on two studies that show the mechanisms behind the activation of the STING protein. Understanding these controls would prevent overactivation of STING which leads to harmful inflammation seen in age-dependent pathology.
By Kat Procyk
A protein called STING is the body’s first round of defense against a multitude of ailments, but it causes harmful inflammation seen in age-dependent pathology, autoinflammatory or neurogenerative conditions when overactivated.
Two new papers in Nature, including one led by Jay Xiaojun Tan, assistant professor of cell biology, School of Medicine, and member of the Aging Institute, University of Pittsburgh, unveiled the mechanisms behind the activation of the STING protein. For an older adult, being able to control STING’s activation could slow age-related decline like memory loss, joint breakdown and heart and blood vessel issues.
When DNA shows up in the cytoplasm—where it doesn’t belong—the cell treats it as a danger signal. This misplaced DNA can appear during infections, cellular stress or age-related diseases. The first protein to notice is cGAS, which acts like the finger that flips a light switch on. As soon as cGAS touches this abnormal DNA, it becomes activated.
Once it’s switched on, cGAS makes a small messenger molecule called cGAMP, acting as an electrical current that flows after the light switch is flipped. Then cGAMP, a ligand, binds to STING, the actual light switch on the wall, effectively turning it on.
When STING turns on, the whole room lights up—meaning a cascade of immune signals is triggered. STING activates IRF3, an interferon regulatory factor, which then turns on genes that produce type I interferons, powerful molecules that alert the immune system to danger.
The DNA sensor cGAS was discovered in 2013 by Zhijian “James” Chen, professor of molecular biology, University of Texas Southwestern Medical Center. Researchers realized that excessive STING activation, triggered by mitochondrial dysfunction or genetic mutations, can overwhelm the cell’s regulatory systems—much like a light bulb blowing out from a power surge—highlighting the need to rein in STING’s antiviral response. However, scientists weren’t entirely certain how this small molecule, cGAMP, was capable of activating STING in the first place.
“When cGAS was first discovered, it was believed the process really was that simple,” said Tan, who was a postdoctoral researcher in Chen’s lab in 2016. “You just turn on the switch and STING is activated, but we’ve recently realized that’s just not enough, and there’s far more to this than we thought.”
A new study published in Nature on Feb. 4, 2026, led by Tan revealed that a lipid called PI(3,5)P₂ also binds to STING and is essential for activation in addition to cGAMP. Neither can work without the other. For example, cGAMP acts as the main light switch, while the lipid functions more like a dimmer that fine-tunes the brightness. An accompanying study in Nature on which Tan also served as an author proved that cholesterol, together with PI(3,5)P₂, is required for STING to oligomerize and fully activate its signaling pathway.
“The lipid essentially guides how STING moves,” explained Chen, who co-led the study with Tan.
Bo Lyu, research assistant professor of cell biology and another member of the Aging Institute through Tan’s lab, added: “And as STING travels, the amount of this lipid steadily rises. If you imagine STING as a light switch, the lipid is what makes the room glow brighter as the switch turns on.”
This two-part mechanism reveals essential processes to precisely understand and control chronic inflammation and eventually develop safer, targeted therapies.