Fig. 4.

Overview of the STING pathway, the involvement of C9orf72 and its relation to C9 ALS/FTD. Cytosolic (mislocalized) TDP-43 species and/or DPR proteins cause mitochondrial damage and lead to the increased production and release of toxic ROS and mitochondrial DNA (mtDNA). cGAS, which is a cytosolic DNA sensor, binds the mtDNA and catalyzes the production of cGAMP which in turn results in stimulator of interferon genes (STING) protein dimerization. STING dimers are able to translocate to the Golgi, where they bind and activate TANK binding kinase 1 (TBK1). This complex will then phosphorylate inhibitor of NF-κBα (IκBα) and interferon regulatory factor 3 (IRF3) and cause both transcription factors to localize to the nucleus and promote the transcription of proinflammatory cytokines and type I interferons. The active STING-TBK1 signalosome is involved in autophagosome formation, an initial step in the process of autophagy. Interestingly, STING is degraded itself by autophagy and thus has an elegant self-regulatory mechanism to control its levels and the activation of the STING-based immune response. Moreover, as C9orf72 is also involved in endolysosomal trafficking and autophagy, reduced levels of the C9orf72 protein may cause a delay or failure of STING degradation and a hyperactivation of the type I interferon response. ATP: adenosine triphosphate; cGAS: cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase; GTP: guanosine triphosphate; IL-6: interleukin 6; IRF3: interferon regulatory factor 3; mtDNA: mitochondrial DNA; NFκB: nuclear factor-κB; OPTN: optineurin; P: phosphorylation; P62: sequestome 1/ ubiquitin-binding protein p62; STING: stimulator of interferon genes; TBK1: TANK binding kinase 1; TDP-43: TAR DNA-binding protein 43; TNF: tumor necrosis factor