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.