Biology subjects

Guo, Q.

Publications and source records attributed to Guo, Q..

At least 91 records · Page 5Linked to original sources

bioRxiv2023

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity

Pathogenic tau accumulation fuels neurodegeneration in Alzheimers disease (AD). Enhancing aging brains resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

neuroscience↗

bioRxiv2023

Structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27-Retromer complex

Endosomal membrane trafficking is mediated by specific protein coats and formation of actin-rich membrane domains. The Retromer complex coordinates with sorting nexin (SNX) cargo adaptors including SNX27, and the SNX27-Retromer assembly interacts with the WASH complex which nucleates actin filaments establishing the endosomal reycling domain. Crystal structures, modelling, biochemical and cellular validation reveal how the FAM21 subunit of WASH interacts with both Retromer and SNX27. FAM21 binds the FERM domain of SNX27 using acidic-Asp-Leu-Phe (aDLF) motifs similar to those found in the SNX1 and SNX2 subunits of the ESCPE-1 complex. Overlapping FAM21 repeats and a specific Pro-Leu containing motif bind three distinct sites on Retromer involving both the VPS35 and VPS29 subunits. Mutation of the major VPS35-binding site does not prevent cargo recycling, however it partially reduces endosomal WASH association indicating that a network of redundant interactions promote endosomal activity of the WASH complex. These studies establish the molecular basis for how SNX27-Retromer is coupled to the WASH complex via overlapping and multiplexed motif-based interactions required for the dynamic assembly of endosomal membrane recycling domains. Significance StatementCell surface transmembrane proteins are regulated by a constant cycle of internalization and recycling from intracellular endosomal compartments. The Retromer protein complex and the sorting nexin adaptor protein play a critical role in the retrieval of hundreds of proteins responsible for ion transport, glucose metabolism, neurotransmission, and other cell functions. We have defined the mechanism by which both Retromer and SNX27 engage the actin-nucleating complex called WASH through multiple repeated sequences in the subunit FAM21. Dysfunction in WASH, Retromer and SNX27 are implicated in various disorders including Parkinsons disease, Alzheimers disease, hereditary spastic paraplegia, and this work provides important insights into the assembly of these essential endosomal sorting machineries.

cell biology↗

bioRxiv2023

Loss of Tumour Suppressor TMEM127 Drives RET-mediated Transformation Through Disrupted Membrane Dynamics

Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTK) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumour pheochromocytoma (PCC) can be caused by activating mutations of the RET receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumour suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization including membrane protein diffusability, and protein complex assembly and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

cancer biology↗

bioRxiv2023

Circulating Small Extracellular Vesicle RNA Profiling for the Detection of T1a stage Colorectal Cancer and Precancerous Advanced Adenoma

It takes more than twenty years for normal colorectal mucosa to develop into metastatic carcinoma. The long time window provides a golden opportunity for early detection to terminate the malignant progression. Here we aim to enable liquid biopsy of T1a stage colorectal cancer (CRC) and precancerous advanced adenoma (AA) by profiling circulating small extracellular vesicle (sEV)-derived RNAs. We exhibited a full RNA landscape for the circulating sEVs isolated from 60 participants. A total of 58,333 annotated RNAs were detected from plasma sEVs, among which 1,615 and 888 sEV-RNAs were found differentially expressed in plasma from T1a stage CRC and AA compared to normal controls (NC). Then we further categorized these sEV-RNAs into 6 modules by a weighted gene coexpression network analysis and constructed a 60-gene t-SNE model consisting of the top 10 RNAs of each module that could well distinguish T1a stage CRC/AA from NC samples. Some sEV-RNAs were also identified as indicators of specific endoscopic and morphological features of different colorectal lesions. The top-ranked biomarkers were further verified by RT-qPCR, proving that these candidate sEV-RNAs successfully identified T1a stage CRC/AA from NC in another cohort of 124 participants. Finally, we adopted different algorithms to improve the performance of RT-qPCR-based models and successfully constructed an optimized classifier with 79.3% specificity and 99.0% sensitivity. In conclusion, circulating sEVs of T1a stage CRC and AA patients have distinct RNA profiles, which successfully enable the detection of both T1a stage CRC and AA via liquid biopsy.

bioinformatics↗

bioRxiv2023

IPEV: Identification of Prokaryotic and Ekaryotic Vrus-derived sequences in virome using deep learning

BackgroundThe virome obtained through virus-like particle enrichment contain a mixture of prokaryotic and eukaryotic virus-derived fragments. Accurate identification and classification of these elements are crucial for understanding their roles and functions in microbial communities. However, the rapid mutation rates of viral genomes pose challenges in developing high-performance tools for classification, potentially limiting downstream analyses. FindingsWe present IPEV, a novel method that combines trinucleotide pair relative distance and frequency with a 2D convolutional neural network for distinguishing prokaryotic and eukaryotic viruses in viromes. Cross-validation assessments of IPEV demonstrate its state-of-the-art precision, significantly improving the F1-score by approximately 22% on an independent test set compared to existing methods when query viruses share less than 30% sequence similarity with known viruses. Furthermore, IPEV outperforms other methods in terms of accuracy on most real virome samples when using sequence alignments as annotations. Notably, IPEV reduces runtime by 50 times compared to existing methods under the same computing configuration. We utilized IPEV to reanalyze longitudinal samples and found that the gut virome exhibits a higher degree of temporal stability than previously observed in persistent personal viromes, providing novel insights into the resilience of the gut virome in individuals. ConclusionsIPEV is a high-performance, user-friendly tool that assists biologists in identifying and classifying prokaryotic and eukaryotic viruses within viromes. The tool is available at https://github.com/basehc/IPEV.

bioinformatics↗

bioRxiv2023

The regulation of Insulin/IGF-1 signaling by miR-142-3p associated with human longevity

MicroRNAs (miRNAs) have been demonstrated to modulate life span in the invertebrates C. elegans and Drosophila by targeting conserved pathways of aging, such as insulin/IGF-1 signaling (IIS). However, a role for miRNAs in modulating human longevity has not been fully explored. Here we investigated novel roles of miRNAs as a major epigenetic component of exceptional longevity in humans. By profiling the miRNAs in B-cells from Ashkenazi Jewish centenarians and 70-year-old controls without a longevity history, we found that the majority of differentially expressed miRNAs were upregulated in centenarians and predicted to modulate the IIS pathway. Notably, decreased IIS activity was found in B cells from centenarians who harbored these upregulated miRNAs. miR-142-3p, the top upregulated miRNA, was verified to dampen the IIS pathway by targeting multiple genes including GNB2, AKT1S1, RHEB and FURIN. Overexpression of miR-142-3p improved the stress resistance under genotoxicity and induced the impairment of cell cycle progression in IMR90 cells. Furthermore, mice injected with a miR-142-3p mimic showed reduced IIS signaling and improved longevity-associated phenotypes including enhanced stress resistance, improved diet/aging-induced glucose intolerance, and longevity-associated change of metabolic profile. These data suggest that miR-142-3p is involved in human longevity through regulating IIS-mediated pro-longevity effects. This study provides strong support for the use of miR-142-3p as a novel therapeutic to promote longevity or prevent aging/aging-related diseases in human.

molecular biology↗

bioRxiv2023

Longevity-associated SMAD3 non-coding centenarian variant impairs a cell-type specific enhancer to reduce inflammation

Given the pro and anti-geronic roles of the TGF-{beta} superfamily in aging, we hypothesized that human longevity involves genetic variation in TGF-{beta} signaling genes. Here we utilized a candidate functional genomic approach to identify and characterize functional variants in TGF- {beta} signaling associated with human longevity. Targeted sequencing of 113 genes involved in aging- associated TGF- {beta} signaling in an Ashkenazi Jewish centenarian cohort identified genetic variants robustly associated with human longevity. In particular, a centenarian-enriched intronic variant residing in a cell-type specific enhancer in SMAD3, a critical receptor-regulated TGF- {beta} signal transducer, was identified. This non-coding SMAD3 variant (rs8040709) altered binding of ELK1, a member of the ETS family of transcription factor important for enhancer activity in certain cell types, resulting in reduced SMAD3 expression. Analysis of the variant in cell types derived from gene edited iPSCs demonstrated the variant reduced SMAD3 expression, senescence and inflammation in endothelial cells. In addition, heterozygosity in SMAD3 improved healthspan and reduced senescence in the Ercc1-/{Delta} progeroid mouse model of accelerated aging. Taken together, these experiments demonstrate that variants in a cell type specific enhancer of SMAD3 resulted in reduced expression, senescence and inflammation and contributes to human longevity. Thus, SMAD3 represents a validated targeted for drug development for extending human healthspan.

genetics↗

bioRxiv2023

Loss of IRF5 increases ribosome biogenesis leading to alterations in mammary gland architecture and metastasis

Despite the progress made in identifying cellular factors and mechanisms that predict progression and metastasis, breast cancer remains the second leading cause of death for women in the US. Using The Cancer Genome Atlas and mouse models of spontaneous and invasive mammary tumorigenesis, we identified that loss of function of interferon regulatory factor 5 (IRF5) is a predictor of metastasis and survival. Histologic analysis of Irf5-/- mammary glands revealed expansion of luminal and myoepithelial cells, loss of organized glandular structure, and altered terminal end budding and migration. RNA-seq and ChIP-seq analyses of primary mammary epithelial cells from Irf5+/+ and Irf5-/-littermate mice revealed IRF5-mediated transcriptional regulation of proteins involved in ribosomal biogenesis. Using an invasive model of breast cancer lacking Irf5, we demonstrate that IRF5 re-expression inhibits tumor growth and metastasis via increased trafficking of tumor infiltrating lymphocytes and altered tumor cell protein synthesis. These findings uncover a new function for IRF5 in the regulation of mammary tumorigenesis and metastasis. HighlightsLoss of IRF5 is a predictor of metastasis and survival in breast cancer. IRF5 contributes to the regulation of ribosome biogenesis in mammary epithelial cells. Loss of IRF5 function in mammary epithelial cells leads to increased protein translation.

cancer biology↗

bioRxiv2023

RNA-binding protein YBX1 promotes Type H vessels dependent bone formation in an m5C-dependent manner

RNA Binding Proteins (RBPs) interact with RNA and ubiquitously regulating RNA transcripts during their life cycle. Previous works showed that RBPs play fundamental roles in the progression of angiogenesis-related diseases. However, the role of RBPs in skeletal endothelium-dependent bone formation and osteogenesis is unclear. Here, we show that RBP-Ybx1 was strongly reduced in bone vasculature from ovariectomy-induced osteoporotic mice. Endothelial cell-specific deletion of Ybx1 impaired CD31hiEMCNhi endothelium morphology and osteogenesis and resulted in low bone mass, while its overexpression promoted angiogenesis-dependent osteogenesis and ameliorated bone loss in OVX mice. Mechanistically, Ybx1 deletion disrupted CD31, EMCN and BMP4 stability in an m5C-dependent manner and blocked endothelial-derived BMP4 release, thereby inhibiting osteogenic differentiation of BMSCs. Administration of recombinant BMP4 protein promoted osteogenic differentiation of BMSCs and restored impaired bone formation in Ybx1i{Delta}EC mice. Finally, tail vein injection of CD31-modified PEG-PLGA carrying sciadopitysin, a natural Ybx1 agonist, pharmacologically partially reversed CD31hiEMCNhi vessels decline and improved the restoration of bone mass both in OVX and aging animals. These findings demonstrated the role of RBP-Ybx1 in angiogenesis-dependent bone formation and provided a novel therapeutic approach for ameliorating aging-related and postmenopausal osteoporosis.

molecular biology↗

bioRxiv2023

Two haplotype-resolved genomes of highly heterozygous AAB allotriploid bananas provide insights into subgenome asymmetric evolution and banana wilt control

Bananas (Musa spp.) are one of the most important tropical fruits and staple food, which are of great significance to human societies. Plantain and Silk are two important banana subgroups, which are both triploid hybrids (AAB) between the wild diploid Musa acuminata and M. balbisiana. In this study, we reported the first haplotype-resolved genome assembly of Plantain and Silk bananas with genome size of approximately 1.4 Gb. We discovered widespread asymmetric evolution in the subgenomes of Plantain and Silk, which could be linked to frequent homologous exchanges (HEs) events. This is the first study to uncover the genetic makeup of triploid banana and verify that subgenome B harbors a rich source of resistance genes. Of the 88,078 and 94,988 annotated genes in Plantain and Silk, only 58.5% and 59.4% were present in all three subgenomes, with >50% genes containing differently expressed alleles in different haplotypes. We also found that Plantain is more resistant to banana Fusarium wilt, exhibiting a much faster defense response after pathogenic fungi infection. Many differentially expressed genes in abscisic acid, ethylene, jasmonic acid and salicylic acid pathways were identified in Plantain. Our analysis revealed that MpMYB36 promotes the biosynthesis of secondary cell wall and deposition of lignin by directly binding to the promoter of MpPAL and MpHCT, which allows Plantain to inhibit the penetration of early infection. Moreover, the insertion of the key carotenoid synthesis gene (CRTISO) may be the potential genetic basis for the richness of carotenoids in Plantain. Our study provides an unprecedented genomic basis for basic research and the development of elite germplasm in cultivated bananas.

plant biology↗

bioRxiv2023

GLI1 facilitates rheumatoid arthritis by collaborative regulation of DNA methyltransferases

Rheumatoid arthritis (RA) is characterized by joint synovitis and bone destruction, the etiology of which remains to be explored. Overactivation of M1 macrophages and osteoclasts has been thought a direct cause of joint inflammation and bone destruction. Glioma-associated oncogene homolog 1 (GLI1) has been revealed to be closely linked to bone metabolism. In this study, GLI1-expression in synovial tissue of RA patients showed to be positively correlated with RA-related scores and was highly expressed in collagen-induced arthritis (CIA) mouse articular macrophage-like cells. The decreased expression and inhibition of nuclear transfer of GLI1 downregulated macrophage M1 polarization and osteoclast activation, the effect of which was achieved by modulation of DNA methyltransferases (DNMTs) via transcriptional regulation and protein interaction ways. By pharmacological inhibition of GLI1, the proportion of proinflammatory macrophages and the number of osteoclasts were significantly reduced, and the joint inflammatory response and bone destruction in CIA mice were alleviated. This study clarified the mechanism of GLI1 in macrophage phenotypic changes and activation of osteoclasts, suggesting potential applications of GLI1 inhibitor in the clinical treatment of RA.

cell biology↗

bioRxiv2023

Bioinformatic analysis of the spike protein cleavage sites of coronaviruses in the mammalian order Eulipotyphla

The mammalian order Eulipotyphla, including hedgehogs and shrews, represent a poorly understood reservoir of coronaviruses with zoonotic potential. Here, we carried out a bioinformatic analyses of these viruses based on the viral spike protein--to illustrate the complexity of coronavirus evolutionary history and the diversity of viruses from these host species, with a focus on the presence of possible furin cleavage sites within the spike protein. We found no evidence for cleavage by furin itself; however, certain strains of Wencheng Sm Shrew coronavirus were shown to have a predicted cleavage site for other member of the proprotein convertases, which are furin family members-- suggesting their spillover potential. As the expanding urbanization and the trade of small mammals in the wet markets enhance the wildlife-human interactions, this may increase pathogen spillover risks. Therefore, we should implement broad wild animal surveillance and be vigilant of contact with these small wild mammals in light of one-health perspectives.

microbiology↗

bioRxiv2022

Individual-specific functional connectivity shows improved performance in detecting and predicting individualized symptoms of Alzheimer's disease in elderly people with/without APOE ε4 allele

To date, no reliable biomarkers are available that link individual-specific functional connectivity and patients individualized symptoms for early detection and prediction of Alzheimers disease (AD) in elderly people with specific genotypes. Meanwhile, functional magnetic resonance imaging (MRI) and machine learning are promising tools that can reveal the relationships between brain and behavior at individual level towards predicting the transition to AD. In this study, individual-specific functional connectivity was constructed in elderly participants with Apolipoprotein E (APOE) {varepsilon}4 allele (N = 120) and without APOE {varepsilon}4 allele (N = 115), respectively. In particular, machine learning based on a recursive feature selection technique was carried out to track multiple clinical symptoms among differing genotypes at individual level from normal aging (NA) and AD. It was found that the captured neuroimaging features in both APOE genotyping groups were able to distinguish the changes of clinical symptoms from NA to AD. Besides, our findings illustrated that the connections between individual-specific functional regions exhibited significantly higher correlation between estimated and observed scores in multiple clinical symptoms than those from atlas-based functional connectivity for both APOE genotyping groups, while no significant performance was detected when the data of two APOE genotyping groups were combined for the estimation models. Further, individual-specific between-network connectivity constitutes a major contributor for accessing cognitive symptoms in both APOE genotyping groups. Therefore, this study demonstrated the essential role of individual variation in cortical functional anatomy and the significance in combining brain and behavior for improving the accuracy in detection and prediction of AD in elderly people with specific genotypes.

neuroscience↗

bioRxiv2022

Systematic characterization of brain cellular crosstalk signaling networks in Alzheimer's disease reveals a novel role for SEMA6D in TREM2-dependent microglial activation

Cellular crosstalk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimers disease (AD). To discover crosstalk dysregulations in AD, we reconstructed crosstalk networks from single-nucleus transcriptional profiles from 67 clinically and neuropathologically well-characterized controls and AD brain donors. We predicted a significant role for TREM2 and additional AD risk genes mediating neuron-microglia crosstalk in AD. The gene sub-network mediating SEMA6D-TREM2 crosstalk is activated near A{beta} plaques and SEMA6D-expressing cells and is disrupted in late AD stages. Using CRISPR-modified human induced pluripotent stem cell-derived microglia, we demonstrated that SEMA6D induces microglial activation in a TREM2-dependent manner. In summary, we demonstrate that characterizing cellular crosstalk networks can yield novel insights into AD biology. One Sentence SummaryWe investigate cell-to-cell communication in Alzheimers disease to characterize disease biology and suggest new avenues for therapeutic intervention.

neuroscience↗

bioRxiv2022

Cellular proteomic profiling using proximity labelling by TurboID-NES in microglial and neuronal cell lines.

1.0Different brain cell types play distinct roles in brain development and disease. Molecular characterization of cell-specific mechanisms using cell type-specific approaches at the protein (proteomic) level, can provide biological and therapeutic insights. To overcome the barriers of conventional isolation-based methods for cell type-specific proteomics, in vivo proteomic labeling with proximity dependent biotinylation of cytosolic proteins using biotin ligase TurboID, coupled with mass spectrometry (MS) of labeled proteins, has emerged as a powerful strategy for cell type-specific proteomics in the native state of cells without need for cellular isolation. To complement in vivo proximity labeling approaches, in vitro studies are needed to ensure that cellular proteomes using the TurboID approach are representative of the whole cell proteome, and capture cellular responses to stimuli without disruption of cellular processes. To address this, we generated murine neuroblastoma (N2A) and microglial (BV2) lines stably expressing cytosolic TurboID to biotinylate the cellular proteome for downstream purification and analysis using MS. TurboID-mediated biotinylation captured 59% of BV2 and 65% of N2A proteomes under homeostatic conditions. TurboID expression and biotinylation minimally impacted homeostatic cellular proteomes of BV2 and N2A cells, and did not affect cytokine production or mitochondrial respiration in BV2 cells under resting or lipopolysaccharide (LPS)-stimulated conditions. These included endo-lysosome, translation, vesicle and signaling proteins in BV2 microglia, and synaptic, neuron projection and microtubule proteins in N2A neurons. The effect of LPS treatment on the microglial proteome was captured by MS analysis of biotinylated proteins (>500 differentially-abundant proteins) including increased canonical pro-inflammatory proteins (Il1a, Irg1, Oasl1) and decrease anti-inflammatory proteins (Arg1, Mgl2).

neuroscience↗

bioRxiv2022

Analysis and Exploration of the Implementation System of Mixed Ownership of Scientific and Technological Achievements in Colleges and Universities

Due to the backwardness of the management model and the rigidity of the system, the current service invention system restricts the transformation of scientific and technological achievements of colleges and universities to a certain extent. The mixed ownership system of university post achievements, which gives universities and inventors the freedom to dispose of the rights of scientific and technological achievements, and fundamentally stimulates the enthusiasm of all the achievement owners to transform their achievements, is an important exploration to promote the transformation of scientific and technological achievements. However, there are still many problems in the implementation of the mixed ownership of scientific and technological achievements in colleges and universities. Through the questionnaire survey and analysis, it is found that the four problems such as defects in the management system for the distribution of rights and interests of scientific and technological achievements, imperfect evaluation indicators of scientific and technological achievements, imbalance in the service system for the transformation of scientific and technological achievements, and lack of authoritative standards for the evaluation of the value of the transformation of scientific and technological achievements are the main problems hindering the development of mixed ownership of the current college post achievements. Based on the existing problems, it is proposed to continue to improve the management system, assessment system and service system of mixed ownership of scientific and technological achievements in colleges and universities. The research results can provide new evidence and policy enlightenment for the development of mixed ownership of scientific and technological achievements in colleges and universities in China.

scientific communication and education↗

bioRxiv2022

Tumor landscape of epithelial ovarian cancer highlights that EGR1 drives tumor invasion at single-cell resolution

Identifying underlying molecular mechanisms and biomarkers of epithelial ovarian carcinoma (EOC) proliferation and metastasis remains challenging. Patients of EOC are usually diagnosed at an advanced stage and the availability of invasion-related targets is limited. Herein, we explored the single-cell RNA sequencing (scRNA-seq) dataset of EOC and defined tumor physiological reprograming compared to bulk RNA-seq. The energy metabolism and anti-apoptotic pathway was found as critical contributors to intratumor heterogeneity. Moreover, hypoxia, oxidative phosphorylation (OXPHOS) and glycolysis were positively correlated, which have biologically activity trajectories during epithelial mesenchymal transition (EMT). The HMGH1, EGR1 and RUNX1 were found to be critical inducers of the EMT process in EOC. Experimental validation revealed that suppressed EGR1 decreased the expression of FAS and HSPG2 and associating with EMT progression in EOC. In tumor microenvironment (TME), CAFs were found have significant contribution to tumor immune infiltration and metastasis and accumulation of CAFs was associated with poorer patient survival. In conclusion, physiological features and molecular mechanisms in the TME of EOC were revealed and provided effective targets for the suppression of tumor metastasis.

bioinformatics↗

bioRxiv2022

The mechanism of DNA sensor cGAS-STING regulating autophagy-related signal pathways

Cyclic GMP-AMP synthase (cGAS) serves as a DNA sensor for recognizing and binding microbial or self-DNA molecules in cells. Upon binding DNA, cGAS produces the second messenger cGAMP to activate the stimulator of interferon genes (STING), which mediates the expression of type 1 interferons (IFN-I) and other cytokines. cGAS-STING-mediated signal pathway plays an important role in innate immune reaction against microbial infections as well as autoimmunity, tumor immunology, and cellular senescence. During this process, cGAS regulates DNA damage repair and induces STING-mediated NF-{kappa}B and MAPK signal pathways in autophagy and lysosome-dependent cell apoptosis. However, the molecular mechanisms of cGAS-STING-mediated autophagy still need to be explored. Here, we found that cGAS-STING promotes autophagy by influencing multiple autophagy-related signal pathways: First, cGAS-STING promotes autophagy by inhibiting the mTOR signaling pathway; Second, cGAS-STING affects autophagy by regulating autophagy-related proteins that are also involved in cGAS-STING-mediated IFN-I and NF-{kappa}B signaling pathways; Third, the Bcl2 can interact with cGAS and STING to induce cGAS-STING-mediated up-regulation of IFN-I signaling pathway and down-regulation of NF-{kappa}B. In addition, we also found that USP19 can significantly reduce the K11-linked ubiquitination of STING in the process of autophagy. Our findings unveiled the functional role and the mechanism of cGAS-STING signaling in regulating autophagy.

molecular biology↗