DNA sensor in standby mode during mitosis

doi:10.1126/science.abg7422

GSTDTAP > 气候变化

DOI	10.1126/science.abg7422
	DNA sensor in standby mode during mitosis
	Andrea Ablasser
	2021-03-19
发表期刊	Science
出版年	2021
英文摘要	Pathogen sensing in innate immunity relies on receptors that must be efficient and precise. To achieve this, cells express various signaling receptors that bind microbial structures, which are absent in the host. In addition, a fascinating mechanism of pathogen sensing is based on the recognition of double-stranded DNA (dsDNA). Coupling such a universal signal to the execution of immune defense not only enables protection against a broad spectrum of pathogens but also allows for the identification of damaged host cells. However, activating immunity to self-DNA can have fatal consequences for the host. What mechanisms guide the critical decision about whether to respond to a DNA molecule? On page 1221 of this issue, Li et al. ([ 1 ][1]) report that cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS)—a major host sensor for dsDNA—exploits phosphorylation and chromatin tethering during mitosis, which abolishes its activity on host genomic DNA. The sensing of dsDNA from the interior of a cell through cGAS can be activated by both foreign and self-DNA ([ 2 ][2]). Upon binding to dsDNA, cGAS synthesizes the second messenger cyclic GMP-AMP (cGAMP), which then activates the endoplasmic reticulum–localized protein stimulator of interferon genes (STING). Activation of STING triggers de novo synthesis of type I interferon genes and multiple proinflammatory mediators, which collectively elicit a potent innate immune response. In addition to detecting infection with pathogens containing dsDNA, the pathway also responds to diverse “sterile” insults, such as the emergence of malignant cells or disruption of tissue homeostasis, and thereby contributes in critical ways to both organismal health and disease. The seemingly indiscriminate sensing capability of cGAS demands auxiliary mechanisms that prevent the enzyme from engaging with self-DNA in healthy cells. Within the cytoplasm, this task is mediated by both DNA-degrading enzymes and the compartmentalization of DNA inside mitochondria. By contrast, within the cell nucleus, cGAS is restricted by tethering to nucleosomes, and chromatin architectural proteins shield genomic DNA from cGAS binding ([ 3 ][3], [ 4 ][4]). However, as cells progress through mitosis, the entire cGAS pool is exposed to the whole nuclear DNA content, with cGAS rapidly associating with mitotic chromosomes ([ 5 ][5], [ 6 ][6]). Whether this particular cell cycle stage afforded additional safeguards complementing the inhibitory role of nucleosomes remained unclear. Li et al. tracked cGAS activity throughout the cell cycle and observed that when isolated from mitotic cells, but not from any other cell cycle stage, the enzyme's capability to synthesize cGAMP was considerably reduced in vitro. This finding was indicative of a specific modification of the cGAS protein itself that could alter its functional properties. Indeed, to properly orchestrate cellular division, many mitotic processes are regulated by rapid and reversible post-translational modifications, one of the most prominent being phosphorylation. That cGAS could be subject to a similar mode of regulation appears an intuitive and appealing solution. Indeed, by monitoring its phosphorylation status, Li et al. showed that cGAS underwent phosphorylation for exactly as long as cells remained in mitosis. Using mass spectrometry analysis, they further revealed multiple mitosis-specific phosphorylation sites, some of which were reliant on the activity of Aurora kinase B, a serine and threonine kinase that is crucially involved in orchestrating mitotic processes. Intriguingly, all phosphorylated residues mapped to the amino-terminal region of cGAS, which is highly disordered and contains multiple positively charged residues known to strengthen its interaction with DNA and thereby promote cGAS phase separation—a process that has been linked to the enzyme's activity ([ 7 ][7], [ 8 ][8]). Could the weakening of ionic interactions between cGAS and DNA through hyperphosphorylation contribute to cGAS silencing during mitosis? Li et al. show that substituting all serine and threonine residues of the cGAS amino terminus with phosphomimetic amino acids severely compromised cGAS phase separation and enzyme activity in vitro. However, a cGAS mutant that could not be phosphorylated at its amino terminus was still suppressed in living mitotic cells. To explain the missing part of regulation, the authors considered the inhibitory effect of nucleosomes, which sequester cGAS primarily through an inhibitory protein-protein interaction contributed by the “acidic patch” of the histone octamer ([ 9 ][9]–[ 14 ][10]). It was predicted that in the nucleosome-bound state, cGAS could neither engage DNA nor oligomerize—two essential steps for enzymatic activation. Consistently, Li et al. demonstrate that defective acidic patch anchoring combined with preventing amino-terminal phosphorylation triggered cGAMP production from mitotic cells. Moreover, the authors showed that cGAS does not oligomerize on mitotic chromosomes in living cells. ![Figure][11] Regulating DNA binding in mitosis In mitotic cells, cGAS associates with chromatin but is inactivated by amino-terminal phosphorylation and nucleosome tethering. In nonmitotic cells, cGAS can be activated by dsDNA in the cytosol, but nucleosome binding and chromatin architectural proteins, such as histone H1 and BAF, restrict cGAS activation in the nucleus. GRAPHIC: C. BICEKL/ SCIENCE Together, this emphasizes the importance of both phosphorylation and inhibitory nucleosome interactions for cGAS inactivation during mitosis (see the figure). Whereas the phosphorylation safeguard negatively affects cGAS DNA interactions and phase separation, nucleosome binding locks cGAS in a monomeric conformation that is unable to bind to DNA. By contrast, upon mitotic exit, the dephosphorylation pattern of cGAS indicates that inhibition inside the nucleus is sufficiently controlled. Yet, in this location, other mechanisms likely take over to enhance the inhibition imparted by nucleosome tethering, including architectural chromatin binding proteins, such as barrier-to-autointegration factor 1 (BAF) and histone H1, which can efficiently suppress the immunogenicity of self-DNA ([ 4 ][4], [ 15 ][12]). With this new insight on the mechanistic basis of cGAS regulation on chromatin, new questions about the interrelationship between DNA sensing and immunity are emerging. For example, could cGAS phosphorylation present yet another immune evasion strategy hijacked by pathogens to propagate infection? Intriguingly, Li et al. report that the amino terminus of cGAS is selectively responsible for chromatin binding but not absolutely necessary to respond to (mitochondrial) DNA. On the basis of this observation, it is tempting to speculate that chromatin recognition by cGAS during mitosis and the attendant nuclear enrichment may serve a beneficial purpose for the host—the nature of which remains to be uncovered. Could disruption of chromatin safeguards also underpin certain pathological processes? Mutations in genes regulating histone de novo synthesis were identified as a cause of the severe autoimmune syndrome Aicardi-Goutières syndrome ([ 15 ][12]). Whether this or another disease can be explained by defects in inhibition of cGAS in response to mitotic or nuclear DNA could ultimately be of medical relevance. Insight into the basics of cGAS-STING pathway regulation may also open possibilities for immunotherapies aimed at boosting immune activation. 1. [↵][13]1. T. Li et al ., Science 371, eabc5386 (2021). [OpenUrl][14][Abstract/FREE Full Text][15] 2. [↵][16]1. A. Ablasser, 2. Z. J. Chen , Science 363, eaat8657 (2019). 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/319924
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Andrea Ablasser. DNA sensor in standby mode during mitosis[J]. Science,2021.
APA	Andrea Ablasser.(2021).DNA sensor in standby mode during mitosis.Science.
MLA	Andrea Ablasser."DNA sensor in standby mode during mitosis".Science (2021).