Detection of microbial DNA is an evolutionarily conserved mechanism that alerts the host immune system to mount a defense response to microbial infections. However, this detection mechanism also ...poses a challenge to the host as to how to distinguish foreign DNA from abundant self-DNA. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is a DNA sensor that triggers innate immune responses through production of the second messenger cyclic GMP-AMP (cGAMP), which binds and activates the adaptor protein STING. However, cGAS can be activated by double-stranded DNA irrespective of the sequence, including self-DNA. Although how cGAS is normally kept inactive in cells is still not well understood, recent research has provided strong evidence that genomic DNA damage leads to cGAS activation to stimulate inflammatory responses. This review summarizes recent findings on how genomic instability and DNA damage trigger cGAS activation and how cGAS serves as a link from DNA damage to inflammation, cellular senescence, and cancer.
Pancreatic cancer is the fourth leading cause of cancer-related death in the United States, with increasing incidence. The mortality rate of pancreatic cancer is rising rapidly, and is projected to ...be the second most common of all malignant tumors by 2030. However, the diagnosis and therapy of pancreatic cancer remain a formidable challenge. Recently, enormous efforts have been made to develop several new methods for the early diagnosis and treatment of pancreatic cancer. We briefly introduce the most groundbreaking advances in pancreatic cancer diagnosis and clinical treatment strategies over the past 15 years, including surgery, chemotherapy, endoscopic therapy, immunotherapy and personalized medicine. The signaling pathways that are altered in the progression of pancreatic cancer, which may be used as therapeutic targets, are also discussed.
Cyclic GMP-AMP (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self DNA in the cytoplasm
. Upon binding DNA, cGAS produces cGAMP that binds to and activates the ...adaptor protein STING, which then activates the kinases IKK and TBK1 to induce interferons and other cytokines
. Here we report that STING also activates autophagy through a mechanism that is independent of TBK1 activation and interferon induction. Upon binding cGAMP, STING translocates to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) and the Golgi in a process that is dependent on the COP-II complex and ARF GTPases. STING-containing ERGIC serves as a membrane source for LC3 lipidation, which is a key step in autophagosome biogenesis. cGAMP induced LC3 lipidation through a pathway that is dependent on WIPI2 and ATG5 but independent of the ULK and VPS34-beclin kinase complexes. Furthermore, we show that cGAMP-induced autophagy is important for the clearance of DNA and viruses in the cytosol. Interestingly, STING from the sea anemone Nematostella vectensis induces autophagy but not interferons in response to stimulation by cGAMP, which suggests that induction of autophagy is a primordial function of the cGAS-STING pathway.
Synaptic transmission is maintained by a delicate, sub-synaptic molecular architecture, and even mild alterations in synapse structure drive functional changes during experience-dependent plasticity ...and pathological disorders. Key to this architecture is how the distribution of presynaptic vesicle fusion sites corresponds to the position of receptors in the postsynaptic density. However, while it has long been recognized that this spatial relationship modulates synaptic strength, it has not been precisely described, owing in part to the limited resolution of light microscopy. Using localization microscopy, here we show that key proteins mediating vesicle priming and fusion are mutually co-enriched within nanometre-scale subregions of the presynaptic active zone. Through development of a new method to map vesicle fusion positions within single synapses in cultured rat hippocampal neurons, we find that action-potential-evoked fusion is guided by this protein gradient and occurs preferentially in confined areas with higher local density of Rab3-interacting molecule (RIM) within the active zones. These presynaptic RIM nanoclusters closely align with concentrated postsynaptic receptors and scaffolding proteins, suggesting the existence of a trans-synaptic molecular 'nanocolumn'. Thus, we propose that the nanoarchitecture of the active zone directs action-potential-evoked vesicle fusion to occur preferentially at sites directly opposing postsynaptic receptor-scaffold ensembles. Remarkably, NMDA receptor activation triggered distinct phases of plasticity in which postsynaptic reorganization was followed by trans-synaptic nanoscale realignment. This architecture suggests a simple organizational principle of central nervous system synapses to maintain and modulate synaptic efficiency.
Random composites with nickel networks hosted randomly in porous alumina are proposed to realize double negative materials. The random composite for DNMs (RC‐DNMs) can be prepared by typical ...processing of material, which makes it possible to explore new DNMs and potential applications, and to feasibly tune their electromagnetic parameters by controlling their composition and microstructure. Hopefully, various new RC‐DNMs with improved performance will be proposed in the future.
TREX1 is an exonuclease that digests DNA in the cytoplasm. Loss-of-function mutations of TREX1 are linked to Aicardi–Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE) in humans.Trex1−/−
...mice exhibit autoimmune and inflammatory phenotypes that are associated with elevated expression of interferon (IFN)-induced genes (ISGs). Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates the IFN pathway. Upon binding to DNA, cGAS is activated to catalyze the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce IFNs and other cytokines. Here we show that genetic ablation ofcGasinTrex1−/−
mice eliminated all detectable pathological and molecular phenotypes, including ISG induction, autoantibody production, aberrant T-cell activation, and lethality. Even deletion of just one allele ofcGaslargely rescued the phenotypes ofTrex1−/−
mice. Similarly, deletion ofcGasin mice lacking DNaseII, a lysosomal enzyme that digests DNA, rescued the lethal autoimmune phenotypes of theDNaseII−/−
mice. Through quantitative mass spectrometry, we found that cGAMP accumulated in mouse tissues deficient in Trex1 or DNaseII and that this accumulation was dependent on cGAS. These results demonstrate that cGAS activation causes the autoimmune diseases inTrex1−/−
andDNaseII−/−
mice and suggest that inhibition of cGASmay lead to prevention and treatment of some human autoimmune diseases caused by self-DNA.
The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) detects microbial and self-DNA in the cytosol to activate immune and inflammatory programs. cGAS also associates ...with chromatin, especially after nuclear envelope breakdown when cells enter mitosis. How cGAS is regulated during cell cycle transition is not clear. Here, we found direct biochemical evidence that cGAS activity was selectively suppressed during mitosis in human cell lines and uncovered two parallel mechanisms underlying this suppression. First, cGAS was hyperphosphorylated at the N terminus by mitotic kinases, including Aurora kinase B. The N terminus of cGAS was critical for sensing nuclear chromatin but not mitochondrial DNA. Chromatin sensing was blocked by hyperphosphorylation. Second, oligomerization of chromatin-bound cGAS, which is required for its activation, was prevented. Together, these mechanisms ensure that cGAS is inactive when associated with chromatin during mitosis, which may help to prevent autoimmune reaction.
Abstract
Magnetars are neutron stars with an extreme magnetic field and sometimes manifest as soft gamma-ray repeaters (SGRs). SGR J1935+2154 is one of the most prolific bursters and the first ...confirmed source of a fast radio burst (FRB; i.e., FRB 200428). Encouraged by the discovery of the first X-ray counterpart of FRBs, the Insight-Hard X-ray Modulation Telescope (Insight-HXMT) implemented a dedicated 33-day-long Target of Opportunity observation of SGR J1935+2154 since 2020 April 28. With the HE, ME, and LE telescopes, Insight-HXMT provides a thorough monitoring of burst activity evolution of SGR J1935+2154, in a very broad energy range (1–250 keV) with high temporal resolution and high sensitivity, resulting in a unique valuable data set for detailed studies of SGR J1935+2154. In this work, we conduct a comprehensive analysis of this observation, including detailed burst search, identification, and temporal analyses. After carefully removing false triggers, we find a total of 75 bursts from SGR J1935+2154, out of which 70 are single pulsed. The maximum burst rate is about 56 bursts day
−1
. Both the burst duration and the waiting time between two successive bursts follow lognormal distributions, consistent with previous studies. We also find that bursts with longer duration (some are multipulsed) tend to occur during the period with relatively high burst rate. There is no correlation between the waiting time and the fluence or duration of either the former or latter burst. It also seems that there is no correlation between burst duration and hardness ratio, in contrast to some previous reports. In addition, we do not find any X-ray burst associated with any reported radio bursts except for FRB 200428.
During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other ...antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.
Abstract
The minimum variation timescale (MVT) of soft gamma-ray repeaters can be an important probe to estimate the emission region in pulsar-like models, as well as the Lorentz factor and radius of ...the possible relativistic jet in gamma-ray burst (GRB)–like models, thus revealing their progenitors and physical mechanisms. In this work, we systematically study the MVTs of hundreds of X-ray bursts (XRBs) from SGR J1935+2154 observed by Insight-HXMT, GECAM, and Fermi/Gamma-ray Burst Monitor from 2014 July to 2022 January through the Bayesian block algorithm. We find that the MVTs peak at ∼2 ms, corresponding to a light-travel time size of about 600 km, which supports the magnetospheric origin in pulsar-like models. The shock radius and the Lorentz factor of the jet are also constrained in GRB-like models. Interestingly, the MVT of the XRB associated with FRB 200428 is ∼70 ms, which is longer than that of most bursts and implies its special radiation mechanism. In addition, the median of MVTs is 7 ms, shorter than the median MVTs of 40 ms and 480 ms for short GRBs or long GRBs, respectively. However, the MVT is independent of duration, similar to GRBs. Finally, we investigate the energy dependence of MVT and suggest that there is a marginal evidence for a power-law relationship like GRBs, but the rate of variation is at least about an order of magnitude smaller. These features may provide an approach to identify bursts with a magnetar origin.
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