Figure caption:
Mechanistic model of the effect of UA. The cGAS-STING pathway plays a central role in innate and adaptive immune defense and is stimulated via a wide variety of cytosolic DNA (1). TREX1 and the indiscriminate degradation of DNA by autophagy modulate the activation of this pathway, but when enough cytosolic DNA is present, it will trigger cGAS to produce cGAMP (2). cGAMP binds to and activates STING, which is upregulated by UA treatment (3, green arrow). STING then translocates from the ER to the Golgi to bind TBK1. TBK1 phosphorylation can activate IRF3 and NF-κB (via IKK), which both translocate to the nucleus to induce the transcription of IFNI and proinflammatory genes (4 and 5). Following UA pretreatment, the IRF3 arm is favored over NF-κB. To modulate STING activation and cytosolic DNA, STING itself promotes autophagosome biogenesis and subsequent recruitment of lipidated LC3 (LC3II), before being degraded via autophagy (6). UA-stimulated STING expression likewise increases autophagic flux and cytosolic DNA clearance.
The cGAS-STING signaling pathway is modulated by urolithin A
Mech Ageing Dev, 2024
DOI: 10.1016/j.mad.2023.111897
During aging, general cellular processes, including autophagic clearance and immunological responses become compromised; therefore, identifying compounds that target these cellular processes is an important approach to improve our health span. The innate immune cGAS-STING pathway has emerged as an important signaling system in the organismal defense against viral and bacterial infections, inflammatory responses to cellular damage, regulation of autophagy, and tumor immunosurveillance. These key functions of the cGAS-STING pathway make it an attractive target for pharmacological intervention in disease treatments and in controlling inflammation and immunity. Here, we show that urolithin A (UA), an ellagic acid metabolite, exerts a profound effect on the expression of STING and enhances cGAS-STING activation and cytosolic DNA clearance in human cell lines. Animal laboratory models and limited human trials have reported no obvious adverse effects of UA administration. Thus, the use of UA alone or in combination with other pharmacological compounds may present a potential therapeutic approach in the treatment of human diseases that involves aberrant activation of the cGAS-STING pathway or accumulation of cytosolic DNA and this warrants further investigation in relevant transgenic animal models.