The human body possesses intricate defense mechanisms to protect against various threats, including infections and cancer. A central component of this innate immune system is the protein STING (STimulator of INterferon Genes). This protein is encoded by the gene TMEM173 and plays a foundational role in recognizing danger signals within cells and initiating protective immune responses.
The STING Protein: A Key Immune Sensor
STING is a protein encoded by the TMEM173 gene. It serves as a vital sensor within the innate immune system, acting as a gatekeeper against intracellular threats. STING is primarily located on the endoplasmic reticulum membrane.
The main function of STING is to detect foreign or misplaced DNA within the cell’s cytoplasm. Normally, DNA is confined to the cell’s nucleus or mitochondria. The presence of DNA in the cytoplasm signals a potential danger, such as from invading viruses, bacteria, or even from the cell’s own damaged components.
How STING Triggers Immunity
STING’s activation is part of the cGAS-STING pathway. This process begins when the enzyme cyclic GMP-AMP synthase (cGAS) detects double-stranded DNA in the cytoplasm. Upon binding, cGAS produces cyclic GMP-AMP (cGAMP).
The cGAMP molecule then binds to and activates STING, which is located on the endoplasmic reticulum. This binding causes STING to undergo a conformational change, leading to its dimerization and translocation from the endoplasmic reticulum to the Golgi apparatus. During this trafficking, activated STING recruits and activates TANK-binding kinase 1 (TBK1).
Activated TBK1 phosphorylates interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 then moves into the cell’s nucleus, where it initiates the production of type I interferons (IFN-I). These interferons alert neighboring cells and orchestrate a broad antiviral and antitumor immune response.
STING in Battling Infections and Cancer
STING’s ability to sense cytosolic DNA makes it a crucial player in the body’s defense. In infections, STING detects the genetic material of invading pathogens like viruses and bacteria in the cytoplasm. STING recognizes DNA from pathogens, triggering type I interferons essential for clearing infections. This activation helps to restrict viral replication and spread.
Beyond infections, STING also contributes to antitumor immunity. Cancer cells release their DNA into the cytoplasm, which the STING pathway recognizes. This recognition leads to the activation of immune cells, including dendritic cells and T cells, which can then target and eliminate tumor cells. STING activation can make tumors more susceptible to immunotherapies by enhancing the body’s anti-cancer response.
When STING Causes Disease
While STING activation is essential for immune defense, its inappropriate or uncontrolled activation can lead to severe health problems. This occurs when the immune system mistakenly reacts to the body’s own DNA, leading to “sterile inflammation.” Such dysregulation can contribute to autoimmune and inflammatory conditions where the immune system attacks healthy tissues.
Mutations in the TMEM173 gene can result in gain-of-function mutations that cause constitutive STING activation. An example is STING-associated vasculopathy with onset in infancy (SAVI), a rare and severe autoinflammatory disorder. SAVI is characterized by systemic inflammation, severe skin lesions, and progressive interstitial lung disease, highlighting the effects of chronic STING overactivity. Other autoimmune diseases, such as systemic lupus erythematosus, have also been linked to aberrant STING pathway activation.
Harnessing STING for New Treatments
The dual role of STING in health and disease has made it an attractive target for therapeutic interventions. Strategies to activate STING are being explored to boost the immune response against cancer and improve vaccine efficacy. STING agonists are under investigation in clinical trials for cancer immunotherapy. These agonists aim to enhance the body’s ability to fight tumors, particularly those resistant to conventional treatments.
Conversely, for conditions caused by STING overactivation, researchers are developing STING inhibitors. These compounds aim to dampen the excessive immune response in autoimmune diseases like SAVI. By blocking STING activity, inhibitors could alleviate inflammation and tissue damage.