cGAS/STING: novel perspectives of the classic pathway
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Molecular Biomedicine
REVIEW
Open Access
cGAS/STING: novel perspectives of the classic pathway Menghui Gao1†, Yuchen He1†, Haosheng Tang1,2, Xiangyu Chen1,2, Shuang Liu3* and Yongguang Tao1,2,4*
Abstract Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor and innate immune response initiator. Binding with exogenous or endogenous nucleic acids, cGAS activates its downstream adaptor, stimulator of interferon genes (STING). STING then triggers protective immune to enable the elimination of the pathogens and the clearance of cancerous cells. Apparently, aberrantly activated by self-DNA, cGAS/STING pathway is threatening to cause autoimmune and inflammatory diseases. The effects of cGAS/STING in defenses against infection and autoimmune diseases have been well studied, still it is worthwhile to discuss the roles of cGAS/STING pathway beyond the “classical” realm of innate immunity. Recent studies have revealed its involvement in non-canonical inflammasome formation, calcium hemostasis regulation, endoplasmic reticulum (ER) stress response, perception of leaking mitochondrial DNA (mtDNA), autophagy induction, cellular senescence and senescence-associated secretory phenotype (SASP) production, providing an exciting area for future exploration. Previous studies generally focused on the function of cGAS/STING pathway in cytoplasm and immune response. In this review, we summarize the latest research of this pathway on the regulation of other physiological process and STING independent reactions to DNA in micronuclei and nuclei. Together, these studies provide a new perspective of cGAS/STING pathway in human diseases. Keywords: cGAS, STING, DNA sensor, Immune, Nuclei, Micronuclei, Tumor, Senescence
Introduction Human body has a complicated defensive system against foreign pathogens, senescent and cancerous cells to maintain internal homeostasis. In this process, correctly detecting aberrant molecules is the first and foremost step, where two main immunity strategies – the adaptive immune system and the innate immune system – play indispensable roles. Adaptive immunity is performed by lymphocytes which are highly specific to a particular pathogen and provide long-lasting protection [1]. Unlike the adaptive immune system, the innate immune system * Correspondence: [email protected]; [email protected] † Menghui Gao and Yuchen He contributed equally to this work. 3 Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China 1 Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, Central South University, Hunan 410078, China Full list of author information is available at the end of the article
is the first line of defense that respond to pathogens in a non-specific and generic way [2]. Extracellular pathogens are sensed and removed after binding to transmembrane receptors such as Toll-like receptors (TLRs), RIG-I
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