Regulation of the cGAS-STING pathway by RNF11

The cGAS-STING pathway is essential for DNA sensing and plays vital roles in host immunity to pathogens and anti-tumor responses. Activation of cGAS-STING needs to be tightly controlled to promote immunity to pathogens and tumors but prevent unrestrained or chronic inflammation that could be detrimental to host fitness. Given that dysregulated or aberrant activation of cGAS-STING by host DNA has been linked to autoimmunity, autoinflammatory diseases, neurodegenerative diseases, and aging-related chronic inflammation, understanding the mechanisms of the negative regulation of cGAS-STING is of critical importance. After binding to its ligand 2’3’-cGAMP, STING traffics from the endoplasmic reticulum (ER) to the Golgi apparatus via coat protein complex II (COPII) vesicles. At the trans-Golgi, STING activates the kinase TBK1 and the transcription factor IRF3 to induce type I interferon (IFN). To ensure transient cGAS-STING activation, STING is sorted post-Golgi by the adaptor protein complex 1 (AP-1) into clathrin-coated vesicles which become encapsulated by lysosomes via ESCRT-mediated microautophagy triggering STING degradation. However, the precise mechanisms controlling COPII-dependent STING trafficking and its negative regulation are largely unknown. In preliminary studies for this exploratory proposal, we provide evidence that the endosomal RING-domain E3 ubiquitin ligase RNF11 functions as a negative regulator of STING activation. RNF11-deficient bone marrow-derived macrophages (BMDMs) exhibit more rapid STING degradation and enhanced STING-induced type I IFN and proinflammatory cytokines. Because RNF11 localizes to early and recycling endosomes and can regulate vesicular trafficking of proteins through COPII vesicles, we hypothesize that RNF11 negatively regulates COPII-mediated STING trafficking from the ER to the Golgi. The goals of this project are to determine the mechanisms of RNF11 regulation of STING (Aim 1), and the role of RNF11 in inhibiting a STING-induced inflammatory response (Aim 2). We anticipate that completion of these studies will provide new insight into the negative regulation of the cGAS-STING pathway which could advance cancer immunotherapies and lead to new treatment strategies for autoimmune, autoinflammatory, and neurodegenerative diseases. Project Number: 1R21AI187996-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: EDWARD HARHAJ | Institution: PENNSYLVANIA STATE UNIV HERSHEY MED CTR, HERSHEY, PA | Award Amount: $425,004 | Activity Code: R21 | Study Section: Innate Immunity and Inflammation Study Section[III] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18799601