STING and liver disease

J Gastroenterol https://doi.org/10.1007/s00535-021-01803-1 REVIEW STING and liver disease Can Chen1 • Rui-Xia Yang1 • Hua-Guo Xu1 Received: 6 May 2021 / Accepted: 18 June 2021 Ó Japanese Society of Gastroenterology 2021 Abstract STING (stimulator of interferon genes) also known as transmembrane protein 173 (TMEM173) is a cytoplasmic DNA sensor which can be activated by the upstream cyclic dinucleotides (CDNs). This activation produces cytokines such as interferons and pro-inflammatory factors via the downstream IRF3 and NF-jB pathways, triggering an innate immune response and adaptive immunity to maintain homeostasis. STING is mainly expressed and activated in non-parenchymal cells, thus exerting a corresponding effect to maintain the homeostasis of the liver. In viral hepatitis, interferons and pro-inflammatory factors produced after STING activation initiate the immune response to inhibit virus replication and assembly. In the case of metabolic diseases of the liver, the activation of STING in kupffer cells and hepatic stellate cells leads to inflammation, the proliferation of connective tissue, and metabolic disorders in the hepatocytes, promoting the occurrence and development of the disease. In hepatocellular carcinoma, STING has two contradictory roles. When STING is activated in dendritic cells and macrophages, a large number of cytokines can be produced to initiate innate immune effects directly and to exert adaptive immunity through the recruitment and activation of T cells; however, aberrant activation of the STING pathway leads to a weakening of immune function and promotes oncogenesis and metastasis. Here, we summarize the Can Chen and Rui-Xia Yang have contributed equally to this work. & Hua-Guo Xu 1 Department of Laboratory Medicine, The First Affiliated Hospital, Nanjing Medical University, 300 Guang Zhou Road, Nanjing 210029, Jiangsu Province, China interactions between STING and liver disease that have currently been identified and how to achieve therapeutic goals by modulating the activity of the STING pathway. Keywords STING
Viral hepatitis
Non-alcoholic fatty liver disease
Liver fibrosis and cirrhosis
Hepatocellular carcinoma Molecular regulation of STING and its signaling pathways STING, also known as MITA, MPYS, ERIS, and TMEM173, is an endoplasmic reticulum (ER) associated dimeric protein that was discovered in 2008 [1–4]. STING consists of an N-terminal domain that spans the ER membrane four times, and a cytoplasmic C-terminal region, which contains the ligand-binding domain (LBD) and the C-terminal tail [5]. STING is mainly distributed in various tissues and organs, and its expression in tissue cells can be controlled by gene regulation. Hypermethylation of CpG land in the STING promoter interferes with STING transcription and downregulates STING expression levels [6]. Transcription factors CREB and c-Myc can combine with human STING (hSTING) promoter to enhance its transcription activity to increase the expression level of STING [7]. STING splicing isoform, including MITA-related protein (MRP), negatively downregulates STINGinduced interferon (IFN) production [8]. MicroRNAs bind to the 3’-untranslated region of hSTING to silence STING translation process and decrease the expression level of STING at the post-transcriptional level [9]. Post-translational modifications (PTMs) of STING can also modulate STING function. Palmitoylation at the STING Cysteine 123 J Gastroenterol 88/91 is critical for the recruitment and activation of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) [10]. In addition to activating STING– TBK1 pathway, which elicits the release of IFNs to exert anti-viral effects, polyubiquitination of STING can also degrade STING and abrogate its effects [11]. TBK1 and IjB kinases (IKK) directly phosphorylate STING and then recruit IRF3 to produce IFNs [12]. In the cytoplasm, activation of STING is mainly through recognition and binding of exogenous cyclic dinucleotides (CDNs) such as cyclic diguanosine monophosphate (c-diGMP) and cyclic diadenylate monophosphate (c-di-AMP) produced by bacteria or endogenous CDNs including cyclic GMP–AMP (cGAMP). When ectopic DNA appears in the cytoplasm, including exogenous DNA produced by viruses and bacteria, and endogenous DNA such as nuclear DNA and mitochondrial DNA, cyclic GMP-AMP synthase (cGAS) as a DNA sensor can detect and bind to cytoplasmic DNA. Subsequently, cGAS is converted to cGAMP, which binds and activates STING [13]. Some RNA viruses trigger the release of cytoplasmic mtDNA to activate cGAS–STING signaling pathway [14]. Upon binding of CDNs, STING undergoes a conformational change and transfers from the ER to the Golgi [15]. Subsequently, STING recruits and activates TBK1 and IRF3, which translocate to the nucleus for transcriptional production of IFNs [1]. STING can also interact with IKK complexes, including IKKa, IKKb, and IKKe. Among them, IKKe can synergistically phosphorylate IRF3 with TBK1, while IKKb and IKKa activate NF- jB [12]. Activated NF-jB dimers enter nucleus to transcribe proinflammatory factors, including IL-1b, IL-6, and TNF-a [12]. Cytokines such as IFNs and pro-inflammatory factors initiate innate immune responses to eliminate intracellular pathogens, and activate antigen-presenting cells (APCs) to cross-presentation antigens to T cells, thereby triggering an adaptive T-cell immune response [1, 12]. In addition, STING activation can induce non-immunological reactions such as cell autophagy, senescence, apoptosis, and necrosis [16] (Fig. 1). STING is not homogeneously distributed in liver. Compared to hepatocytes, STING is mainly expressed and activated in hepatic non-parenchymal cells (NPCs), including Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells (HSCs). Exogenous pathogens mainly infect hepatocytes, so the effects of STING in liver are mainly exerted through cellular cross-talking [17]. This review summarizes the current interaction between STING and liver diseases and how to exogenously regulate STING activity to achieve therapeutic effects. 123 Viral hepatitis type B HBV is an enveloped double-stranded DNA virus and HBV genomic DNA is a relaxed circular double-stranded DNA molecule (rcDNA). After HBV invades hepatocytes, HBV genome enters the nucleus, at which point rcDNA is extended and converted into covalently closed circular DNA (ccDNA). HBV uses cccDNA as a template to transcribe four mRNA. The longest 3.5 kb fragment is called pre-genomic RNA (pgRNA), carrying all genetic information. The pgRNA is used as a template to generate offspring rcDNA to form a new HBV [18]. Currently, it has been shown that STING activation can produce IFNs to inhibit HBV replication [19–24]. The polymerase polymorphism rt269I in HBV genotype C and telomerase-derived 16-mer peptide GV1001 cause mitochondrial stress and release mtDNA in human HCC cell line HepG2, which activates STING–TBK1–IRF3 pathway an (...truncated)