DNA sensor cGAS-mediated immune recognition

Abstract

The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types. cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) from adenosine triphosphate and guanosine triphosphate. cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon production. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs.

Keywords: DNA sensors; cGAMP; cGAS; cytosolic DNAs; innate immunity.

Figure 1

Signaling pathways of cytosolic DNA sensors with DNA challenge. Up to now, many cytosolic DNA sensors have been defined to detect intracellular double-stranded DNAs. RNA polymerase III transcribes AT-rich DNAs into RNAs that are recognized by RNA sensor RIG-I, followed by STING and IRF3 activation. DNA sensors DAI, IFI16, DDX41 and LSm14A sense dsDNA directly to activate STING for type I IFN production. In the presence of dsDNAs, cGAS catalyzes the synthesis of cGAMP, a strong activator of STING. With dsDNAs, LRRFIP1 initiates β-catenin and IRF3 activation in a STING-dependent manner. Other DNA sensors prime immune responses independently of STING. After recognition of dsDNAs, Sox2 triggers the activation of the Tab2/TAK1 complex in neutrophils. When detected by dsDNAs, DHX9/36 activates NFκB and IRF7 through MyD88. DNA sensor Ku70 triggers the activation of IRF1 and IRF7. AIM2 initiates the activation of inflammasome through ASC with DNA binding

Figure 2

Structural basis of cGAS binding to DNA. In a resting state, cGAS exists with a monomer form. The DNA binding site comprises helices that form a flat spine. Post DNA binding, cGAS forms dimerization and undergoes conformational changes that render the spine region twisted, promoting synthesis of cGAMP. Inset is an illustration of cGAS activation upon binding DNA

Figure 3

cGAS mediates dsDNA recognition and its regulation. cGAS is essential for immune recognition of foreign DNAs from various sources, such as DNA viruses, retroviruses and intracellular bacteria. cGAS activity is tightly regulated to prevent excessive activation. Besides host modifiers of cGAS, microbes possess various molecules to inhibit cGAS activity for their survival