Optineurin calibrates STING-mediated type I interferon response

Cyclic GMP-AMP synthase (cGAS) senses cytosolic self and microbial DNA to produce cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a secondary messenger that activates the endoplasmic reticulum-resident transmembrane protein, stimulator of interferon genes (STING). After binding to cGAMP, STING undergoes oligomerisation, exits the endoplasmic reticulum (ER), recruits tank-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) on Golgi membranes, resulting in the activation of type I interferons (IFNs). STING is found to be a preformed dimer in the ER; however, it is yet unknown whether protein-protein interactions maintain STING in its resting state. Optineurin (OPTN) functions as an adaptor or a scaffold to coordinate autophagy, type I IFN response, vesicle trafficking, and mitophagy. TBK1 commonly binds OPTN and STING to activate type I IFNs in response to extracellular and intracellular cues. However, it remains unclear whether OPTN participates in STING-mediated type I interferon (IFN) response. As STING initiates inflammatory signalling and OPTN functions as an adaptor protein, we asked if OPTN is necessary for STING to mediate type I IFN response. To answer this question, we examined STING-mediated type I IFN response in human and mouse cells depleted of OPTN and elucidated STING-OPTN binding. We found that modulating OPTN levels alters STING-mediated type I IFN response. Further, the N-terminal domain of STING binds to the C-terminal ubiquitin-binding domain of OPTN. In addition, we found that OPTN engages with STING and TBK1. Thus, we conclude that OPTN calibrates STING-mediated type I IFN response. Based on our observations, approaches that include developing tailored molecular glue-like compounds binding STING-OPTN, and determining STING activation might be valuable avenues for understanding and treating autoimmune diseases.