title: STING signalling pathway in SLE and the potential role of cGAMP transfer
title: The STING signalling pathway in SLE and the potential role of cGAMP transfer
titleType: AlternativeTitle
Creators: name: Costello, Jonathan
Publisher: name: The University of Edinburgh
Year: 2022
Subjects: subject: STING (Stimulator of Interferon genes)
subject: STING Signalling Pathway
subject: signalling adaptor protein
subject: detection of cytosolic nucleic acids
subject: cytosolic enzymatic sensor cGAS (cyclic GMP-AMP synthase)
subject: cytosolic dsDNA
subject: cGAMP
subject: endoplasmic reticulum
subject: 1 IFN (interferon) response
subject: ISGs (interferon-stimulated genes)
subject: SLE lymphocytes

description: STING (Stimulator of Interferon genes) is a signalling adaptor protein that serves in the detection of cytosolic nucleic acids. Upstream components of the canonical STING pathway include the cytosolic enzymatic sensor cGAS (cyclic GMP-AMP synthase) which produces cGAMP (cyclic guanosine monophosphate–adenosine monophosphate) on exposure to cytosolic dsDNA. The second messenger cGAMP transmits the detection of dsDNA by activating STING on the endoplasmic reticulum (ER). STING activation induces a type 1 IFN (interferon) response leading to the upregulation of ISGs (interferon-stimulated genes) which promote the effector functions of immune cells. The major source of ISG induction under normal circumstances is in the presence of microbial infection. The transcription of ISGs establishes an anti-viral state to combat multiple aspects of infection. Besides having anti-viral functions, STING signalling is essential in many physiological processes such as cell proliferation, genomic stability, autophagy, and metabolic homeostasis to name a few. However, aberrant STING-dependent type 1 IFN production is also implicated in numerous diseases. One notable example is the autoimmune disease SLE (systemic lupus erythematosus). Defective clearance of self-antigens such as dsDNA represents a major source of STING activation in SLE. This causes excessive type 1 IFN production which breaks immune tolerance against self which sustains autoimmunity in SLE. The transfer of cGAMP to bystander cells also represents a possible mechanism for STING activation in SLE. This mechanism has been studied largely in the area of cancer research, as the insufficient STING signalling observed in many cancers contributes to immunosuppressive tumour microenvironments. This is because STING is often anti-tumorigenic by detecting increased cytosolic dsDNA typical of cancerous cells and promoting immune cell infiltration and tumour death. The transfer of cGAMP to bystander cells may allow STING activation to still occur in such cancers. However, the alternative ‘cell-extrinsic’ STING activation, may be highly deleterious in autoimmune disease. Preliminary results from Dr. Mohini Gray’s group suggest that the hyperactivated STING signalling in lupus lymphocytes is transferred to bystander cells in vitro. The Gray group has contributed to the knowledge of STING signalling in SLE by identifying a novel role for SLE lymphocytes. Aberrant STING signalling in SLE lymphocyte signalling likely contributes to lupus disease in a cell-intrinsic and a cell-extrinsic manner. Overall, it is suspected that STING signalling is a common pathway in pathogenesis of autoimmune diseases and cancer. Further research into dysregulated STING signalling, cGAMP transfer and in the development of STING directed therapies may have disease cross-over potential.