Biology subjects

Feng, Y.

Publications and source records attributed to Feng, Y..

At least 325 records · Page 18Linked to original sources

bioRxiv2020

X-chromosome dosage compensation dynamics in human early embryos

In mammals, female cells are obliged to inactivate one of two X chromosomes to achieve dosage parity with the single X chromosome in male cells, and it is also thought that the single active X chromosome is increased 2-fold to achieve dosage balance with two sets of autosomes (X:A ratio = 1, or Ohnos hypothesis). However, the ontogeny of X-chromosome inactivation and augmentation of the single active X remains unclear during human embryogenesis. Here, we perform single-cell RNA-seq analysis to examine the timing of X:A balancing and X-inactivation (XCI) in pre- and peri-implantation human embryos up to fourteen days in culture. We find that X-chromosome gene expression in both male and female preimplantation embryos is approximately balanced with autosomes (X:A ratio = 1) after embryonic genome activation (EGA) and persists through fourteen days in vitro. Cross-species analysis of preimplantation embryo also show balanced X:A ratio within the first few days of development. By single-cell mRNA SNP profiling, we find XCI beginning in day 6-7 blastocyst embryos, but does not affect X:A dosage balance. XCI is most evident in trophoectoderm (TE) cells, but can also be observed in a small number of inner cell mass (ICM)-derived cells including primitive endoderm (PE) and epiblast (EPI) cells. Analysis between individual XaXa and XaXi sister cells from the same embryo reveals random XCI and persistently balanced X:A ratio, including sister cells transitioning between XaXa and XaXi states. We therefore conclude that the male X-chromosome undergoes X chromosome augmentation prior to the simultaneous X-chromosome inactivation and augmentation in females. Together, our data demonstrate an evolutionally conserved model of X chromosome dosage compensation in humans and other mammalian species.

developmental biology↗

bioRxiv2020

A New tet(X6) Tigecycline Resistance Determinant Co-carried with mcr-1 by A Single Plasmid

Tigecycline and colistin are few of last-resort defenses used in anti-infection therapies against carbapenem-resistant bacterial pathogens. The successive emergence of plasmid-borne tet(X) tigecycline resistance mechanism and mobile colistin resistance (mcr) determinant, renders them clinically ineffective, posing a risky challenge to global public health. Here, we report that co-carriage of tet(X6) and mcr-1 gives co-resistance to both classes of antibiotics by a single plasmid in E. coli. Genomic analysis suggested that transposal transfer of mcr-1 proceeds into the plasmid pMS8345A, in which a new variant tet(X6) is neighbored with Class I integron. The structure-guided mutagenesis finely revealed the genetic determinants of Tet(X6) in the context of phenotypic tigecycline resistance. The combined evidence in vitro and in vivo demonstrated its enzymatic action of Tet(X6) in the destruction of tigecycline. The presence of Tet(X6) (and/or MCR-1) robustly prevents the accumulation of reactive oxygen species (ROS) induced by tigecycline (and/or colistin). Unlike that mcr-1 exerts fitness cost in E. coli, tet(X6) does not. In the tet(X6)-positive strain that co-harbors mcr-1, tigecycline resistance is independently of colistin resistance caused by MCR-1-mediated lipid A remodeling, and vice versa. Co-production of Tet(X6) and MCR-1 gives no synergistic delayed growth of the recipient E. coli. Similar to that MCR-1 behaves in the infection model of G. mellonella, Tet(X6) renders the treatment of tigecycline ineffective. Therefore, co-transfer of such two AMR genes is of great concern in the context of "one health" comprising environmental/animal/human sectors, and heightened efforts are required to monitor its dissemination. Author summaryWe report that tet(X6), a new tigecycline resistance gene, is co-carried with the other resistance gene mcr-1 by a single plasmid. Not only have we finely mapped genetic determinants of tet(X6), but also revealed its biochemical action of tigecycline destruction. Crosstalk of Tet(X6) with MCR-1 is addressed. Tet(X6) tigecycline resistance is independently of MCR-1 colistin resistance, and vice versa. Similar to MCR-1 that renders colistin clinically ineffective, Tet(X6) leads to the failure of tigecycline treatment in the infection model of G. mellonella. This study extends mechanistic understanding mechanism and interplay of Tet(X6) and MCR-1, coproduced by a single plasmid. It also heightens the need to prevent rapid and large-scaled spread of AMR.

biochemistry↗

bioRxiv2020

Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus in China (SARS-CoV-2)

A new coronavirus SARS-CoV-2 has caused over 9.2 million infection cases and 475758 deaths worldwide. Due to the rapid dissemination and the unavailability of specific therapy, there is a desperate need for vaccines to combat the epidemic of SARS-CoV-2. An in silico approach based on the available virus genome was applied to identify 19 high immunogenic B-cell epitopes and 499 human-leukocyte-antigen (HLA) restricted T-cell epitopes. Thirty multi-epitope peptide vaccines were designed by iNeo Suite, and manufactured by solid-phase synthesis. Docking analysis showed stable hydrogen bonds of epitopes with their corresponding HLA alleles. When four vaccine peptide candidates from the spike protein of SARS-CoV-2 were selected to immunize mice, a significantly larger amount of IgG in serum as well as an increase of CD19+ cells in ILNs was observed in peptide-immunized mice compared to the control mice. The ratio of IFN-{gamma}-secreting lymphocytes in CD4+ or CD8+ cells in the peptides-immunized mice were higher than that in the control mice. There were also a larger number of IFN-{gamma}-secreting T cells in spleen in the peptides-immunized mice. This study screened antigenic B-cell and T-cell epitopes in all encoded proteins of SARS-CoV-2, and further designed multi-epitope based peptide vaccine against viral structural proteins. The obtained vaccine peptides successfully elicited specific humoral and cellular immune responses in mice. Primate experiments and clinical trial are urgently required to validate the efficacy and safety of these vaccine peptides. ImportanceSo far, a new coronavirus SARS-CoV-2 has caused over 9.2 million infection cases and 475758 deaths worldwide. Due to the rapid dissemination and the unavailability of specific therapy, there is a desperate need for vaccines to combat the epidemic of SARS-CoV-2. Different from the development approaches for traditional vaccines, the development of our peptide vaccine is faster and simpler. In this study, we performed an in silico approach to identify the antigenic B-cell epitopes and human-leukocyte-antigen (HLA) restricted T-cell epitopes, and designed a panel of multi-epitope peptide vaccines. The resulting SARS-CoV-2 multi-epitope peptide vaccine could elicit specific humoral and cellular immune responses in mice efficiently, displaying its great potential in our fight of COVID-19.

bioinformatics↗

bioRxiv2020

Glucose-mediated expansion of a gut commensal bacterium promotes Plasmodium infection through alkalizing mosquito midgut

SUMMARYDietary sugar is the major energy source for mosquitoes, but its influence on mosquitoes capability to transmit malaria parasite remains unclear. Here we show that Plasmodium berghei infection changes global metabolism of Anopheles stephensi with the most significant impact on glucose metabolism. Supplementation of glucose or trehalose (the main hemolymph sugar) to mosquito increases Plasmodium infection by alkalizing the mosquito midgut. The glucose/trehalose diets promote rapid growth of a commensal bacterium, Asaia bogorensis, which remodels glucose metabolism and consequently increases midgut pH. The pH increase in turn promotes Plasmodium gametogenesis. We also demonstrate the sugar composition from different natural plants influences A. bogorensis growth and Plasmodium infection is associated with their capability to expand A. bogorensis. Altogether, our results demonstrate that dietary glucose is an important factor that determines mosquitos competency to transmit Plasmodium and further highlight a key role for mosquito-microbiota metabolic interactions in regulating development of malaria parasite.

microbiology↗

bioRxiv2020

Isolation and Characterization of 2019-nCoV-like Coronavirus from Malayan Pangolins

The outbreak of 2019-nCoV in the central Chinese city of Wuhan at the end of 2019 poses unprecedent public health challenges to both China and the rest world1. The new coronavirus shares high sequence identity to SARS-CoV and a newly identified bat coronavirus2. While bats may be the reservoir host for various coronaviruses, whether 2019-nCoV has other hosts is still ambiguous. In this study, one coronavirus isolated from Malayan pangolins showed 100%, 98.2%, 96.7% and 90.4% amino acid identity with 2019-nCoV in the E, M, N and S genes, respectively. In particular, the receptor-binding domain of the S protein of the Pangolin-CoV is virtually identical to that of 2019-nCoV, with one amino acid difference. Comparison of available genomes suggests 2019-nCoV might have originated from the recombination of a Pangolin-CoV-like virus with a Bat-CoV-RaTG13-like virus. Infected pangolins showed clinical signs and histopathological changes, and the circulating antibodies reacted with the S protein of 2019-nCoV. The isolation of a coronavirus that is highly related to 2019-nCoV in the pangolins suggests that these animals have the potential to act as the intermediate host of 2019-nCoV. The newly identified coronavirus in the most-trafficked mammal could represent a continuous threat to public health if wildlife trade is not effectively controlled.

microbiology↗

bioRxiv2020

CRISPR-based Live Imaging of Epigenetic Modification-Mediated Genome Reorganization

Epigenetic modifications play an essential role in chromatin architecture and dynamics. The role of epigenetic modification in chromatin organization has been studied by Hi-C from population cells, but imaging techniques to study their correlation and regulation in single living cells are lacking. Here we develop a CRISPR-based EpiGo (Epigenetic perturbation induced Genome organization) system to track epigenetic modification-mediated relocation, interaction or reorganization of genomic regions in living cells. EpiGo-KRAB is sufficient to induce the relocation of genomic loci to HP1 condensates and trigger genomic interactions. EpiGo-KRAB also triggers the induction of H3K9me3 at large genomic regions, which decorate on the surface of HP1 condensates possibly driven by phase separation.

molecular biology↗

bioRxiv2020

Spatial and functional links between cellular virological state and progression of liver fibrosis in chronic hepatitis B

Chronic Hepatitis B Virus (HBV) infection is strongly associated with the progression of liver fibrosis, cirrhosis and hepatocellular carcinoma. Despite intensive study, the detailed mechanisms leading to HBV induced liver disease have not been fully elucidated. Previously, we reported a mosaic distribution of viral antigens and nucleic acids at single-cell level in liver tissues of chronic hepatitis B (CHB) patients and proposed a three-stage model of HBV infection in vivo. Here, we explored whether the different stages at cellular level is functionally linked with fibrogenesis. We observed a tight spatial relationship between the invasion of collagen fibers and transitions from S-rich to DNA-rich stage. While S-rich cells mainly localized within minimally fibrotic tissue, DNA-rich cells were often closely surrounded by a milieu of stiffened extracellular matrix (ECM). cDNA microarray and subsequent validation analyses revealed that S-rich cells manifested elevated ribosomal proteins and oxidative phosphorylation genes in a disease phase-dependent manner. On the other hand, DNA-rich cells exhibited gradually deteriorated expression of hepatocyte-specific antigen and transcriptional regulator in parallel with the progression of hepatic fibrosis. Finally, during fibrogenesis, inflammatory genes such as IP-10 were found to be expressed in both portal infiltrated cells and surrounding parenchymal cells which resulted in suppressed antigen expression. Taken together, we propose that liver inflammation and accompanying fibrogenesis is spatially and functionally linked with the transition of virological stages at cellular level. These transitions occur possibly due to an altered hepatocyte transcription profile in response to a transformed ECM environment. The collective viral and host activities shape the histological alterations and progression of liver disease during CHB infection.

microbiology↗

bioRxiv2020

Carbamazepine restores neuronal signaling, protein synthesis and cognitive function in a mouse model of fragile X syndrome

Fragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, it is widely accepted that the lack of FMRP causes elevated protein synthesis and deregulation of neuronal signaling. Abnormal enhancement of the ERK[1/2] (extracellular signal-regulated kinase [1/2]) and PI3K-Akt (Phosphoinositide 3 kinase-protein kinase B) signaling pathways has been identified in both FXS patients and FXS mouse models. In this study, we show that carbamazepine, which is an FDA-approved drug and has been mainly used to treat seizure and neuropathic pain, corrects cognitive deficits including passive avoidance and object location memory in FXS mice. Carbamazepine also rescues hyper locomotion and social deficits. At the cellular level, carbamazepine dampens the elevated level of ERK[1/2] and Akt signaling as well as protein synthesis in FXS mouse neurons. Together, these results advocate repurposing carbamazepine for FXS treatment.

neuroscience↗

bioRxiv2020

Regulation of HDAC2-PDX1 by RNF125 defines pancreatic cancer development

There is an urgent need to define mechanisms underlying pancreatic adenocarcinoma (PDA) development. Our studies of ubiquitin ligases that may underlie PDA development led us to identify and characterize RNF125. We show that RNF125 exhibits nuclear expression in acinar cells, with reduced and largely cytosolic expression in ductal cells, PanIN and PDA specimens. We find that RNF125 interacts with histone deacetylase 2 (HDAC2) and promotes its non-canonical K63-linked ubiquitination. Inhibition of HDAC2 activity by RNF125 resulted in elevated expression of the pancreatic and duodenal homeobox 1 (PDX1). Correspondingly, inhibition of RNF125 expression enhanced organoid growth in culture and orthotopic tumor development. Conversely, restoration of PDX1 levels in human or mouse PDA cells and organoids depleted of RNF125, inhibited cell proliferation and growth, while expression of HDAC2 enhanced it. Notably, higher expression of RNF125 and PDX1 coincided with differentiated tumor phenotypes, and better outcome in PDA patients. In demonstrating the importance of RNF125 control of PDX1 expression via HDAC2 ubiquitination in PDA development, our findings highlight markers (RNF125, PDX1) and targets (HDAC2) for monitoring and possible treatment of PDA.

cancer biology↗

bioRxiv2019

Reconstructing the evolutionary origins of extreme halophilic Archaeal lineages

Interest and controversy surrounding the evolutionary origins of extremely halophilic Archaea has increased in recent years, due to the discovery and characterization of the Nanohaloarchaea and the Methanonatronarchaeia. Initial attempts in explaining the evolutionary placement of the two new lineages in relation to the classical Halobacteria (also referred to as Haloarchaea) resulted in hypotheses that imply the new groups share a common ancestor with the Haloarchaea. However, more recent analyses have led to a shift: the Nanohaloarchaea have been largely accepted as being a member of the DPANN superphylum, outside of the euryarchaeota; while the Methanonatronarchaeia have been placed near the base of the Methanotecta (composed of the class II methanogens, the Halobacteriales, and Archaeoglobales). These opposing hypotheses have far-reaching implications on the concepts of convergent evolution (unrelated groups evolve similar strategies for survival), genome reduction, and gene transfer. In this work, we attempt to resolve these conflicts with phylogenetic and phylogenomic data. We provide a robust taxonomic sampling of Archaeal genomes that spans the Asgardarchaea, TACK Group, euryarchaeota, and the DPANN superphylum. In addition, we assembled draft genomes from seven new representatives of the Nanohaloarchaea from distinct geographic locations. Phylogenies derived from these data imply that the highly conserved ATP synthase catalytic/non-catalytic subunits of Nanohaloarchaea share a sisterhood relationship with the Haloarchaea. We also employ a novel gene family distance clustering strategy which shows this sisterhood relationship is not likely the result of a recent gene transfer. In addition, we present and evaluate data that argue for and against the monophyly of the DPANN superphylum, in particular, the inclusion of the Nanohaloarchaea in DPANN. Significance StatementMany recent analyses have considered large groups of Bacteria and Archaea composed exclusively of environmentally assembled genomes as deep branching taxonomic groups in their respective domains. These groups display characteristics distinct from other members of their domain, which can attract unrelated lineages into those groups. This manuscript evaluates the case of the Nanohaloarchaea, and their inclusion in the DPANN Archaea, through careful analysis of the genes that compose the core of the Nanohaloarchaea. Analyses without inspection of the genes that compose a phylogenomic marker set increases the potential for the inclusion of artifacts and confuses the tree/web of life. Due to horizontal gene transfer and phylogenetic reconstruction artifacts, the placement of divergent archaeal classes into larger groups remains uncertain.

microbiology↗

bioRxiv2019

Molecular basis of differential parasitism between non-encapsulated and encapsulated Trichinella revealed by a high-quality genome assembly

Understanding roles of repetitive sequences in genomes of parasites could offer insights into their evolution, speciation, and parasitism. As a unique intracellular nematode, Trichinella consists of two clades, encapsulated and non-encapsulated. Genomic correlation to the distinct differences between the two clades is still unclear. Here we report an annotated draft reference genome of non-encapsulated Trichinella, T. pseudospiralis, and performed comparative analyses with encapsulated T. spiralis. Genome analysis revealed that, during Trichinella evolution, repetitive sequence insertions played an important role in gene family expansion in synergy with DNA methylation, especially for the DNase II members of the phospholipase D superfamily and Glutathione S-transferases. We further identify the genomic and epigenomic regulation of excretory/secretory products in relation to differences in parasitism, pathology and immunology between the two clades Trichinella. The present study provided a foundation for further elucidation of mechanism of nurse cell formation and immunoevasion as well as identification of phamarcological and diagnostic targets of trichinellosis.

genomics↗

bioRxiv2019

The stepwise endonuclease activity of a thermophilic Argonaute protein

Thermophilic Argonaute proteins (Agos) can function as endonucleases via specific guide-target base-pairing cleavage for host defense. The ability to cleave target DNA sequences at any arbitrary sites endows them with reprogramed DNA capacity. Here, we identify that an Ago from the hyperthermophilic archaeon Pyrococcus furiosus (PfAgo) shows a stepwise endonuclease activity, which is demonstrated by the double strand DNA cleavage directed by a single guide DNA rather than canonical one pair of guide DNAs. We reveal that the cleavage products with 5-phosphorylated ends can used as the renewed guide which is capable to induce next round of cleavage to complementary sequences of target DNA. By combining the PfAgo stepwise endonuclease activity followed by target DNA amplification, we establish a rapid and specific platform for the unambiguously multiplex gene detection, termed RADAR (Renewed-gDNA Assisted DNA-cleavage by Argonaute). In the end, RADAR was applied to distinguish of human papillomavirus of serotypes in patient samples in a single reaction, suggesting that our technique would be adopted for diagnosing application.

bioengineering↗

bioRxiv2019

A-Star, an Argonaute-directed System for Rare SNV Enrichment and Detection

The ability to detect rare mutations has revolutionized diagnosis and monitoring of tumors, but is limited by the shortage of sensitive, cost-effective and high coverage methods for identification of extremely low abundant mutations. Here, we establish a single-tube multiplex PCR system by employing thermophilic Argonaute-derived DNA-guided nuclease for highly efficient rare mutation detection, referred to as A-Star (Argonaute-directed specific target enrichment and detection), that combines the selective cleavage of the wild type DNA in the DNA denaturation step and the followed amplification of mutant DNA during PCR. A-Star enables easy detection and quantitation of rare mutations originally as low as 0.01% in allele frequency with a [>=] 5500-fold efficiency. We also demonstrate the feasibility of A-Star for detecting oncogenic mutations in complex biological systems such as solid tumors tissues and blood samples. Remarkably, A-Star could achieve the detection of multiple oncogenic genes simultaneously through a simple single-tube reaction. Taken together, our work illustrates a supersensitive and rapid nucleic acid detection system, thereby extending the utility for both research and therapeutic applications.

bioengineering↗

bioRxiv2019

The Study on Computer Vision-Assisted Cell Bank Construction and Screening & Classification

Computer vision technology plays an important role in screening and culturing cells. This paper proposes a method to construct a helper cell library based on cell image segmentation and screening. Firstly, cell culture and image acquisition were carried out. The main content is to use laboratory conditions to carry out different cell types. Through careful observation of the whole process of cell proliferation and passage, the representative pictures of different stages were taken. Analysis and summary of the relevant morphology, texture, color characteristics. Secondly, computer vision technology is used to segment cells and extract the main features such as cell perimeter and area. Explore the automatic information extraction method of cell bank, and complete the image segmentation of individual cell image from the whole picture. Finally, the cells were screened and identified. Investigate different pattern recognition methods and neural network structures, and prepare pictures of various cell pictures. The corresponding neural network and prediction program are constructed. This paper proposes an automatic image processing method for each image category in cell culture cycle, which improves the automation of production process. At the same time, compared with the design of a single algorithm for a certain type of cell, different algorithm design ideas are proposed for three types of pictures with different characteristics, which is closer to the dynamic change of cell morphology in the process of cell culture. This research has important application prospects in promoting cell factory research, cell bank construction and automatic screening.

bioinformatics↗

bioRxiv2019

Crl activates transcription by stabilizing the active conformation of the master stress factor σS

{sigma}S is a master transcription initiation factor that protects bacterial cells from various harmful environmental stresses and antibiotic pressure. Although its mechanism remains unclear, it is known that full activation of {sigma}S-mediated transcription requires a {sigma}S-specific activator, Crl. In this study, we determined a 3.80 [A] cryo-EM structure of an E. coli transcription activation complex (E. coli Crl-TAC) comprising E. coli {sigma}S-RNAP holoenzyme, Crl, and a nucleic-acid scaffold. The structure reveals that Crl interacts with the domain 2 of {sigma}S ({sigma}S2), sharing no interaction with promoter DNA. Subsequent hydrogen-deuterium exchange mass spectrometry (HDX-MS) results indicate that Crl stabilizes key structural motifs of {sigma}S2 to promote the assembly of {sigma}S-RNAP holoenzyme and also to facilitate formation of the RNA polymerase-promoter DNA open complex (RPo). Our study demonstrates a unique DNA contact-independent mechanism of transcription activation, thereby defining a previously unrecognized mode of transcription activation in cells.

biochemistry↗

bioRxiv2019

An integrative ENCODE resource for cancer genomics

ENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types. A key aspect of this annotation is comprehensive and experimentally derived networks of both transcription factors and RNA-binding proteins (TFs and RBPs). Cancer, a disease of system-wide dysregulation, is an ideal application for such a network-based annotation. Specifically, for cancer-associated cell types, we put regulators into hierarchies and measure their network change (rewiring) during oncogenesis. We also extensively survey TF-RBP crosstalk, highlighting how SUB1, a previously uncharacterized RBP, drives aberrant tumor expression and amplifies the effect of MYC, a well-known oncogenic TF. Furthermore, we show how our annotation allows us to place oncogenic transformations in the context of a broad cell space; here, many normal-to-tumor transitions move towards a stem-like state, while oncogene knockdowns show an opposing trend. Finally, we organize the resource into a coherent workflow to prioritize key elements and variants, in addition to regulators. We showcase the application of this prioritization to somatic burdening, cancer differential expression and GWAS. Targeted validations of the prioritized regulators, elements and variants using siRNA knockdowns, CRISPR-based editing, and luciferase assays demonstrate the value of the ENCODE resource.

genomics↗

bioRxiv2019

Computational analysis of transcriptome signature repurposes low dose trifluoperazine for the treatment of fragile X syndrome in mouse model

Fragile X syndrome (FXS), caused by mutations in fragile X mental retardation 1 gene (FMR1), is a prevailing genetic disorder of intellectual disability and autism. Currently, there is no efficacious medication for FXS. Here, we use transcriptome landscape as a holistic molecular phenotype/endpoint to identify potential therapeutic intervention. Through in silico screening with public gene signature database, computational analysis of transcriptome profile in Fmr1 knockout (KO) neurons predicts therapeutic value of an FDA-approved drug trifluoperazine. Through experimental validation, we find that systemic administration of low dose trifluoperazine at 0.05 mg/kg attenuates multiple FXS- and autism-related behavioral symptoms. Moreover, computational analysis of transcriptome alteration caused by trifluoperazine suggests a new mechanism of action against PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) activity. Consistently, trifluoperazine suppresses PI3K activity and its down-stream targets Akt (protein kinase B) and S6K1 (S6 kinase 1) in neurons. Further, trifluoperazine normalizes the aberrantly elevated activity of Akt and S6K1 and enhanced protein synthesis in FXS mouse. In conclusion, our data demonstrate promising value of gene signature-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders, and suggest trifluoperazine as a potential practical treatment for FXS.

neuroscience↗

bioRxiv2019

STING recruits NLRP3 to the ER and deubiquitinates NLRP3 to activate the inflammasome

One of the fundamental reactions of the innate immune responses to pathogen infection is the release of pro-inflammatory cytokines, including IL-1{beta}, processed by the NLRP3 inflammasome. STING is essential for innate immune responses and inflammasome activation. Here we reveal a distinct mechanism by which STING regulates the NLRP3 inflammasome activation, IL-1{beta} secretion, and inflammatory responses in human cell lines, mice primary cells, and mice. Interestingly, upon HSV-1 infection and cytosolic DNA stimulation, STING binds to NLRP3 and promotes the inflammasome activation through two approaches. First, STING recruits NLRP3 and promotes NLRP3 translocation to the endoplasmic reticulum, thereby facilitating the inflammasome formation. Second, STING interacts with NLRP3 and removes K48- and K63-linked polyubiquitination of NLRP3, thereby promoting the inflammasome activation. Collectively, we demonstrate that the cGAS-STING-NLRP3 signaling is essential for host defense against DNA virus infection.

immunology↗