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When STING Meets Viruses: Sensing, Trafficking Andesponse R Washington University School of Medicine Digital Commons@Becker Open Access Publications 1-1-2020 When STING meets viruses: Sensing, trafficking andesponse r Zhaohe Li Siqi Cai Yutong Sun Li Li Siyuan Ding See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors Zhaohe Li, Siqi Cai, Yutong Sun, Li Li, Siyuan Ding, and Xin Wang fimmu-11-02064 September 25, 2020 Time: 19:58 # 1 REVIEW published: 29 September 2020 doi: 10.3389/fimmu.2020.02064 When STING Meets Viruses: Sensing, Trafficking and Response Zhaohe Li1, Siqi Cai1, Yutong Sun1, Li Li1,2,3, Siyuan Ding4 and Xin Wang1,2,3* 1 Key Laboratory of Marine Drugs of Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China, 2 Center for Innovation Marine Drug Screening and Evaluation, Pilot National Laboratory for Marine Science and Technology, Qingdao, China, 3 Marine Biomedical Research Institute of Qingdao, Qingdao, China, 4 Department of Molecular Microbiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States To effectively defend against microbial pathogens, the host cells mount antiviral innate immune responses by producing interferons (IFNs), and hundreds of IFN-stimulated genes (ISGs). Upon recognition of cytoplasmic viral or bacterial DNAs and abnormal endogenous DNAs, the DNA sensor cGAS synthesizes 2’,3’-cGAMP that induces STING (stimulator of interferon genes) undergoing conformational changes, cellular trafficking, and the activation of downstream factors. Therefore, STING plays a pivotal role in preventing microbial pathogen infection by sensing DNAs during pathogen invasion. This review is dedicated to the recent advances in the dynamic regulations of STING activation, intracellular trafficking, and post-translational modifications (PTMs) Edited by: by the host and microbial proteins. Chunfu Zheng, Fujian Medical University, China Keywords: STING, DNA viruses, cellular trafficking, post translational modifications, immune responses Reviewed by: Qi Wang, Harbin Veterinary Research Institute INTRODUCTION (CAS), China Junji Xing, The immune response is a complicated process in which the body defends against pathogen Houston Methodist Research infections and confines the disease progression, leading to the eventual recovery, and conferring Institute, United States protective immunity. Innate immunity is the first line to resist viral invasion. A myriad of host *Correspondence: factors, such as interferons (IFNs), cytokines, and chemokines, respond quickly to viral invading, Xin Wang and trigger adaptive immunity (1). Due to the special biological features of viruses and their unique [email protected] relationships with host cells, antiviral immunity not only shares commonalities with antibacterial immunity but also has unique characteristics. Invading viruses trigger innate immunity during and Specialty section: after entry into host cells via germline-encoded molecules termed pattern recognition receptors This article was submitted to (PRRs), which detect pathogens by recognition of their conserved molecular structures, called Viral Immunology, a section of the journal pathogen-associated molecular patterns (PAMPs) (2). In this process, different PRRs jointly Frontiers in Immunology participate in the complicated and delicate immune responses by collaboration between multiple Received: 02 June 2020 PRRs and their downstream factors. Until now, stimulator of interferon genes (STING) is the most Accepted: 29 July 2020 important adaptor protein in immune responses against DNA viruses, in cooperation with other Published: 29 September 2020 well-identified molecules, including cGAS, TBK1, IRF3, and NF-kB(3–5). Citation: Li Z, Cai S, Sun Y, Li L, Ding S and Wang X (2020) When STING DNA VIRUS INFECTION, IMMUNE RESPONSE, AND DISEASES Meets Viruses: Sensing, Trafficking and Response. To date, more than 6,000 types of viruses have been identified according to the International Front. Immunol. 11:2064. Committee on Taxonomy of Viruses (ICTV). There are approximately 400 kinds of viruses of doi: 10.3389/fimmu.2020.02064 human health concerns and many are double-stranded DNA (dsDNA) viruses or retroviruses. Frontiers in Immunology| www.frontiersin.org 1 September 2020| Volume 11| Article 2064 fimmu-11-02064 September 25, 2020 Time: 19:58 # 2 Li et al. STING Immune Response For instance, the retrovirus human immunodeficient virus are also the major producers of IFNs in the peripheral blood (HIV) is considered as a DNA virus here because of the (25, 26). viral dsDNA produced by reverse transcription process, leading to Acquired Immune Deficiency Syndrome (AIDS). Similarly, chronic infection with human hepatitis B virus CELLULAR SENSORS OF ABNORMAL (HBV), which is harboring a partial double-stranded DNA genomic DNA and belongs to Hepadnaviridae, leads to liver fibrosis and cancers (6). Other pathogenic human Several DNA sensing PRRs have been characterized so far, DNA viruses mostly belong to the Poxviridae, Herpesviridae, including Toll-like receptors (TLRs), NOD-like receptors Adenoviridae, Papillomaviridae, and Polyomaviridae families. (NLRs), C-type lectin receptors (CLRs), and cytosolic DNA In the Herpesviridae family, human cytomegalovirus (HCMV) sensors including cyclic GMP–AMP synthase (cGAS), IFN-g causes immunocompromised symptoms of the brain, liver, (IFN-g)-inducible protein 16 (IFI16), heterogeneous nuclear spleen, and lung (7). Infection by the herpes simplex virus ribonucleoprotein A2/B1 (hnRNPA2B1), absent in melanoma 1 (HSV-1) results in painful blisters or ulcers (8). What’s 2 (AIM2), DNA-dependent activator of IRFs (DAI), RNA more, it might lead to more serious symptoms including polymerase III, DEAD box helicase 41 (DDX41), DEAH box encephalitis. HSV-2 infection is a typical sexually transmitted protein 9 (DHX9)/DEAH box protein 36 (DHX36), leucine-rich disease (STD) with the symptom of different genital warts repeat flightless-interacting protein 1 (LRRFIP1), Ku70, and Sox2 (9). Epstein-Barr virus (EBV) is involved in numerous types (3, 27, 28). As the first discovered DNA recognition molecule, of lymphomas and gastric cancers (10). Kaposi’s sarcoma– DAI binds to dsDNA and induces type I IFN (IFN-I) (29, 30). associated herpesvirus (KSHV) is found in Kaposi’s sarcoma, However, the knockdown of DAI does not affect the innate primary effusion lymphoma, and multicentric Castleman’s immune response of mice to B-DNA stimulation in later studies, disease. The incidence of Kaposi’s sarcoma is much higher raising controversy (31). AIM2 is an IFN induced cytosolic in immunosuppressed individuals, because of the deficiency protein containing a pyrin domain (PYD) and a HIN200 of host immunity (10, 11). Especially, Kaposi’s sarcoma domain. The HIN domain promotes its binding to DNA. The has a high fatality rate among AIDS patients (12). Virulent PYD binds to ASC, the apoptosis-associated speck-like protein adenoviruses lead to the common cold, fever, sore throat, containing a caspase recruitment domain (CARD), forming acute bronchitis, pneumonia, and neurologic disease (in an activated caspase-1 inflammasome to promote releases of rare cases) (13–15, 187). In the Papillomaviridae and IL-1b, and IL-18 (32). RNA polymerase III converts dsDNA poly Polyomaviridae families, high-risk human papillomaviruses (dA:dT) into 50- triphosphate double-stranded RNA, delivering (HPVs) are admittedly oncogenic and significantly related signals to the RIG-I pathway (33, 34). DDX41 (DEAD box to cervical cancer and head and neck cancers (16), while polypeptide 41) promotes IFN and IFN-stimulated genes (ISGs) low-risk HPVs are responsible for anogenital condyloma, expression in a STING-dependent way. It recognizes intracellular genital warts, and other skin diseases (17). Merkle cell DNA or bacterial c-di-GMP and c-di-AMP and then activates polyomavirus (MCPyV) integration is found in Merkle cell IRF3 by TBK1 (35, 36). IFI16 is predominantly a nuclear protein carcinoma. JC polyomavirus and BK polyomavirus are found sensing abnormal DNA in the nucleus (37). HnRNPA2B1 is in organ transplant patients (18, 19). Therefore, a thorough another recently reported nuclear initiation factor that detects understanding of the arms race between DNA viruses and and limits DNA virus infection (38). host immunity is required to develop therapeutic strategies for Potentiating signals from many other DNA sensors and viral infections. cyclic dinucleotides (CDNs) binding, places STING a nodal Innate immunity is vital to restrict viral infections at the position to restrict DNA viruses. The first promised DNA early stages of host antiviral immunity (20). After the invasion, sensor IFI16 implicating in IFN induction by DNA stimulation viral PAMPs stimulate IFN production in a variety of cells, localizes both in the nucleus and the cytoplasm but may sense which possess a broad-spectrum antiviral effect (21). Thus, abnormal DNA in the nucleus (39), because HSV-1 ICP0 re- they would induce antiviral albumin to block viral propagation localizes IFI16 from the nucleus to the cytoplasm, hampering (22). For innate immune responses to viral invasion, although IFN responses to viruses (40). Active IFI16 recruits STING PRRs and IFN signaling are constituently components in nearly to facilitate a TBK1-dependent gene induction. Knockdown all somatic cells to control early infections in our body, it of IFI16 or its mouse ortholog p204 impairs IFN-I induction is believed that leukocytes are the protagonists
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