“Exploring the SERCA2-STING Connection in Inflammatory and metabolic responses” – STORM

The cGAS-STING pathway is a key component of the innate immune system, primarily recognized for promoting inflammatory responses. Our recent findings indicate that STING also plays a vital role in metabolic homeostasis by regulating delta-6-desaturase (FADS2), an enzyme critical for synthesizing polyunsaturated fatty acids (PUFAs). I have identified a novel connection between STING and the SERCA2 (Sarco/Endoplasmic Reticulum Ca2+ ATPase 2) pump, which regulates calcium influx into the endoplasmic reticulum (ER), where STING is inactive. Although STING activity has been linked to calcium fluxes, the role of a calcium pump in this process has not yet been explored.

Preliminary data indicate that inhibiting SERCA2 enhances STING-mediated inflammation, likely through altered calcium fluxes or changes in SERCA2 conformation. The first objective of the STORM project is to investigate the molecular mechanisms governing the interaction between SERCA2 and STING, specifically whether SERCA2’s regulation of STING activation depends on Ca2+ flux or conformational changes. This research will elucidate the complex interplay between SERCA2 function, STING-driven inflammation, and cellular metabolism.

Mutations in SERCA2 have been associated with Darier disease, characterized by skin abnormalities, chronic inflammation, and metabolic disruptions, including altered PUFA profiles. This suggests a potential link between SERCA2 dysfunction, abnormal STING activity, and metabolic imbalances. We will utilize an in vitro model of SERCA2 mutations to examine how these mutations impact STING activation and metabolic processes in Darier disease. This research aims to uncover new mechanisms connecting inflammation and metabolic dysregulation, potentially providing new therapeutic targets. Ultimately, this project seeks to connect innate immune responses with metabolic regulation by investigating STING’s novel role in controlling metabolic pathways through its interaction with SERCA2.