Miz1 represses type I interferon production and limits viral clearance during influenza A virus infection.

Type I interferons (IFNs) are critical for the antiviral immune response, and fine-tuning type I IFN production is critical to effectively clearing viruses without causing harmful immunopathology. We showed that the transcription factor Miz1 epigenetically repressed the expression of genes encoding type I IFNs in mouse lung epithelial cells by recruiting histone deacetylase 1 (HDAC1) to the promoters of Ifna and Ifnb. Loss of function of Miz1 resulted in augmented production of these type I IFNs during influenza A virus (IAV) infection, leading to improved viral clearance in vitro and in vivo. IAV infection induced Miz1 accumulation by promoting the cullin-4B (CUL4B)-mediated ubiquitylation and degradation of the E3 ubiquitin ligase Mule (Mcl-1 ubiquitin ligase E3; also known as Huwe1 or Arf-BP1), which targets Miz1 for degradation. As a result, Miz1 accumulation limited type I IFN production and favored viral replication. This study reveals a previously unrecognized function of Miz1 in regulating antiviral defense and a potential mechanism for influenza viruses to evade host immune defense.

Novel potential lncRNA biomarker in B cells indicates essential pathogenic pathway activation in patients with SLE.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a highly heterogeneous disease, and B cell abnormalities play a central role in the pathogenesis of SLE. Long non-coding RNAs (lncRNAs) have also been implicated in the pathogenesis of SLE. The expression of lncRNAs is finely regulated and cell-type dependent, so we aimed to identify B cell-expressing lncRNAs as biomarkers for SLE, and to explore their ability to reflect the status of SLE critical pathway and disease activity. METHODS: Weighted gene coexpression network analysis (WGCNA) was used to cluster B cell-expressing genes of patients with SLE into different gene modules and relate them to clinical features. Based on the results of WGCNA, candidate lncRNA levels were further explored in public bulk and single-cell RNA-sequencing data. In another independent cohort, the levels of the candidate were detected by RT-qPCR and the correlation with disease activity was analysed. RESULTS: WGCNA analysis revealed one gene module significantly correlated with clinical features, which was enriched in type I interferon (IFN) pathway. Among non-coding genes in this module, lncRNA RP11-273G15.2 was differentially expressed in all five subsets of B cells from patients with SLE compared with healthy controls and other autoimmune diseases. RT-qPCR validated that RP11-273G15.2 was highly expressed in SLE B cells and positively correlated with IFN scores (r=0.7329, p<0.0001) and disease activity (r=0.4710, p=0.0005). CONCLUSION: RP11-273G15.2 could act as a diagnostic and disease activity monitoring biomarker for SLE, which might have the potential to guide clinical management.

African swine fever virus pB318L, a trans-geranylgeranyl-diphosphate synthase, negatively regulates cGAS-STING and IFNAR-JAK-STAT signaling pathways.

African swine fever (ASF) is an acute, hemorrhagic, and severe infectious disease caused by the ASF virus (ASFV). ASFV has evolved multiple strategies to escape host antiviral immune responses. Here, we reported that ASFV pB318L, a trans-geranylgeranyl-diphosphate synthase, reduced the expression of type I interferon (IFN-I) and IFN-stimulated genes (ISGs). Mechanically, pB318L not only interacted with STING to reduce the translocation of STING from the endoplasmic reticulum to the Golgi apparatus but also interacted with IFN receptors to reduce the interaction of IFNAR1/TYK2 and IFNAR2/JAK1. Of note, ASFV with interruption of B318L gene (ASFV-intB318L) infected PAMs produces more IFN-I and ISGs than that in PAMs infected with its parental ASFV HLJ/18 at the late stage of infection. Consistently, the pathogenicity of ASFV-intB318L is attenuated in piglets compared with its parental virus. Taken together, our data reveal that B318L gene may partially affect ASFV pathogenicity by reducing the production of IFN-I and ISGs. This study provides a clue to design antiviral agents or live attenuated vaccines to prevent and control ASF.

Antiviral activity of adenoviral vector expressing human interferon lambda-4 against influenza virus.

Interferon lambda (IFNλ), classified as a type III IFN, is a representative cytokine that plays an important role in innate immunity along with type I IFN. IFNλ can elicit antiviral states by inducing peculiar sets of IFN-stimulated genes (ISGs). In this study, an adenoviral vector expression system with a tetracycline operator system was used to express human IFNλ4 in cells and mice. The formation of recombinant adenovirus (rAd-huIFNλ4) was confirmed using immunohistochemistry assays and transmission electron microscopy. Its purity was verified by quantifying host cell DNA and host cell proteins, as well as by confirming the absence of the replication-competent adenovirus. The transduction of rAd-huIFNλ4 induced ISGs and inhibited four subtypes of the influenza virus in both mouse-derived (LA-4) and human-derived cells (A549). The antiviral state was confirmed in BALB/c mice following intranasal inoculation with 109 PFU of rAd-huIFNλ4, which led to the inhibition of four subtypes of the influenza virus in mouse lungs, with reduced inflammatory lesions. These results imply that human IFNλ4 could induce antiviral status by modulating ISG expression in mice.

IFI16 Positively Regulates RIG-I-Mediated Type I Interferon Production in a STING-Independent Manner.

Previous studies have shown that interferon gene-stimulating protein (STING) is essential for IFN-γ-inducible protein 16 (IFI16) as the DNA sensor and RNA sensor to induce transcription of type I interferon (IFN-I) and is essential for IFI16 to synergize with DNA sensor GMP-AMP (cGAMP) synthase (cGAS) in induction of IFN-I transcription. While other and our previous studies have shown that IFI16 enhanced retinoic acid-inducible gene I (RIG-I)-, which was an RNA sensor, and mitochondrial antiviral signaling (MAVS)-, which was the adaptor protein of RIG-I, induced production of IFN-I, so we wonder whether IFI16 regulates the signal pathway of RNA-RIG-I-MAVS-IFN-I in a STING-dependent manner. We used HEK 293T cells, which did not express endogenous STING and were unable to mount an innate immune response upon DNA transfection and found that IFI16 could enhance RIG-I- and MAVS-mediated induction of IFN-I in a STING-independent way. Furthermore, we found that upregulation of the expression of NF-kappa-B essential modulator (NEMO) by IFI16 was not the mechanism that IFI16 regulated the induction of IFN-I. In conclusion, we found that IFI16 regulated the signal pathway of RNA-RIG-I-MAVS-IFN-I in a STING-independent manner.

Type I interferon pathway activation across the antiphospholipid syndrome spectrum: associations with disease subsets and systemic antiphospholipid syndrome presentation.

Introduction: While the type I interferon (IFN-I) pathway is crucial in autoimmunity, its role in antiphospholipid antibody (aPL)-positive subjects, including aPL carriers and antiphospholipid syndrome (APS) patients, is poorly understood. This study aims at characterizing IFN-I pathway activation within the spectrum of aPL-positive subsets. Methods: A total of 112 patients [29 aPL carriers, 31 primary APS (PAPS), 25 secondary APS (SAPS), 27 systemic lupus erythematosus (SLE) patients without aPL, and 44 healthy controls (HCs)] were recruited. IFI6, IFI44, IFI44L, MX1, IFI27, OAS1, and RSAD2 gene expression was evaluated in whole blood, and a composite index (IFN score) was calculated. Results: An overall activation of the IFN-I pathway was observed across the entire APS spectrum, with differences among genes based on the specific disease subset. The composite score revealed quantitative differences across subsets, being elevated in aPL carriers and PAPS patients compared to HCs (both p < 0.050) and increasing in SAPS (p < 0.010) and SLE patients (p < 0.001). An unsupervised cluster analysis identified three clusters, and correspondence analyses revealed differences in clusters usage across APS subsets (p < 0.001). A network analysis revealed different patterns characterizing different subsets. The associations between IFN-I pathway activation and clinical outcomes differed across APS subsets. Although no differences in gene expression were observed in systemic APS, the network analyses revealed specific gene-gene patterns, and a distinct distribution of the clusters previously identified was noted (p = 0.002). Conclusion: IFN-I pathway activation is a common hallmark among aPL-positive individuals. Qualitative and quantitative differences across the APS spectrum can be identified, leading to the identification of distinct IFN-I signatures with different clinical values beyond traditional categorization.

Type I interferon associated epistasis may contribute to early disease-onset and high disease activity in juvenile-onset lupus.

Pathologic type I interferon (T1IFN) expression is a key feature in systemic lupus erythematosus (SLE) that associates with disease activity. When compared to adult-onset disease, juvenile-onset (j)SLE is characterized by increased disease activity and damage, which likely relates to increased genetic burden. To identify T1IFN-associated gene polymorphisms (TLR7, IRAK1, miR-3142/miR-146a, IRF5, IRF7, IFIH1, IRF8, TYK2, STAT4), identify long-range linkage disequilibrium and gene:gene interrelations, 319 jSLE patients were genotyped using panel sequencing. Coupling phenotypic quantitative trait loci (QTL) analysis identified 10 jSLE QTL that associated with young age at onset (<12 years; IRAK1 [rs1059702], TLR7 [rs3853839], IFIH1 [rs11891191, rs1990760, rs3747517], STAT4 [rs3021866], TYK2 [rs280501], IRF8 [rs1568391, rs6638]), global disease activity (SLEDAI-2 K >10; IFIH1 [rs1990760], STAT4 [rs3021866], IRF8 [rs903202, rs1568391, rs6638]), and mucocutaneous involvement (TLR7 [rs3853839], IFIH1 [rs11891191, rs1990760]). This study suggests T1IFN-associated polymorphisms and gene:gene interrelations in jSLE. Genotyping of jSLE patients may allow for individualized treatment and care.

UMP-CMP kinase 2 inhibits ZIKV replication through activation of type I IFN signaling pathway.

Cytidine/uridine monophosphate kinase 2 (UMP-CMP kinase 2, CMPK2) has been reported as an antiviral interferon-stimulated gene (ISG). We previously observed that the expression of CMPK2 was significantly upregulated after Zika Virus (ZIKV) infection in A549 cells. However, the association and the underlying mechanisms between CMPK2 induction and ZIKV replication remain to be determined. We investigated the induction of CMPK2 during ZIKV infection and the effect of CMPK2 on ZIKV replication in A549, U251, Vero, IFNAR-deficient U5A and its parental 2fTGH cells, Huh7 and its RIG-I-deficient derivatives Huh7.5.1 cells. The activation status of Jak-STAT signaling pathway was determined by detecting the phosphorylation level of STAT1, the activity of interferon stimulated response element (ISRE) and the expression of several interferon stimulated genes (ISGs). We found that ZIKV infection induced CMPK2 expression through an IFNAR and RIG-I dependent manner. Overexpression of CMPK2 inhibited while CMPK2 knockdown promoted ZIKV replication in A549 and U251 cells. Mechanically, we found that CMPK2 overexpression increased IFNß expression and activated Jak/STAT signaling pathway as shown by the increased level of p-STAT1, enhanced activity of ISRE, and the upregulated expression of downstream ISGs. These findings suggest that ZIKV infection induced CMPK2 expression, which inhibited ZIKV replication and serves as a positive feedback regulator for IFN-Jak/STAT pathway.

Identification of the shared hub gene signatures and molecular mechanisms between HIV-1 and pulmonary arterial hypertension.

The close link between HIV-1 infection and the occurrence of pulmonary arterial hypertension (PAH). However, the underlying molecular mechanisms of their interrelation remain unclear. The microarray data of HIV-1 and PAH were downloaded from GEO database. We utilized WGCNA to identify shared genes between HIV-1 and PAH, followed by conducting GO and pathway enrichment analyses. Subsequently, differentially genes analysis was performed using external validation datasets to further filter hub genes. Immunoinfiltration analysis was performed using CIBERSORT. Finally, hub gene expression was validated using scRNA-seq data. We identified 109 shared genes through WGCNA, primarily enriched in type I interferon (IFN) pathways. By taking the intersection of WGCNA important module genes and DEGs, ISG15 and IFI27 were identified as pivotal hub genes. Immunoinfiltration analysis and scRNA-seq results indicated the significant role of monocytes in the shared molecular mechanisms of HIV-1 and PAH. In summary, our study illustrated the possible mechanism of PAH secondary to HIV-1 and showed that the heightened IFN response in HIV-1 might be a crucial susceptibility factor for PAH, with monocytes being pivotal cells involved in the type I IFN response pathway. This provides potential new insights for further investigating the molecular mechanisms connecting HIV-1 and PAH.

Identification of Nonfunctional Alternatively Spliced Isoforms of STING in Human Acute Myeloid Leukemia.

Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I IFN responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro tools to evaluate the efficacy of novel STING agonists, we found most AML lines to be poor producers of IFNs upon exposure to extremely potent agonists, suggesting cell-intrinsic suppression of STING signaling may occur. We observed unexpected patterns of response that did not correlate with levels of STING pathway components or of known enzymes associated with resistance. To identify a genetic basis for these observations, we cloned and sequenced STING from the cDNA of human AML cell lines and found both frequent mutations and deviations from normal RNA splicing. We identified two novel spliced isoforms of STING in these lines and validated their expression in primary human AML samples. When transduced into reporter cells, these novel STING isoforms exhibited complete insensitivity to agonist stimulation. These observations identify alternative splicing as a mechanism of STING pathway suppression and suggest that most AML silences the STING pathway through direct modification rather than through engagement of external inhibitory factors. SIGNIFICANCE: We find that AML acquires resistance to innate immune activation via the STING pathway through aberrant splicing of the STING transcript including two novel forms described herein that act as dominant negatives. These data broaden understanding of how cancers evolve STING resistance, and suggest that the AML tumor microenvironment, not the cancer cell, should be the target of therapeutic interventions to activate STING.

Enzymatic activity of cGAS in the presence of three types of DNAs: limited cGAS stimulation by single-stranded HIV-1 SL2 DNA.

Cyclic GMP-AMP (cGAMP) synthase (cGAS) is activated by binding to DNA. Activated cGAS produces 2'3'-cGAMP, which subsequently binds to the adaptor protein STING (stimulator of interferon genes). This interaction triggers the cGAS/STING signaling pathway, leading to the production of type I interferons. Three types of DNA, namely double-stranded DNA longer than 40 base pairs, a 70-nucleotide single-stranded HIV-1 DNA known as SL2, and Y-form DNA with unpaired guanosine trimers (G3 Y-form DNA), induce interferon production by activating cGAS/STING signaling. However, the extent of cGAS activation by each specific DNA type remains unclear. The comparison of cGAS stimulation by various DNAs is crucial for understanding the mechanisms underlying cGAS-mediated type I interferon production in the innate immune response. Here, we revealed that cGAS produces 2'3'-cGAMP at a significantly lower rate in the presence of single-stranded SL2 DNA than in the presence of double-stranded DNA or G3 Y-form DNA. Furthermore, the guanine-to-cytosine mutations and the deletion of unpaired guanosine trimers significantly reduced the 2'3'-cGAMP production rate and the binding of cGAS to Y-form DNA. These studies will provide new insights into the cGAS-mediated DNA-sensing in immune response.

A cluster of type I interferon-regulated genes associates with disease activity and prognosis in patients with IgA nephropathy.

The exact pathogenesis of IgA nephropathy (IgAN) is complex and so far, not well defined. Since it has been shown that microbial infections could induce high levels of type I interferon (IFN-I) and there is an evident link between mucosal infection and gross hematuria in IgAN, we hypothesized that IFN-I may play a role in the pathogenic process. In this study, we investigated the type I interferon status in IgAN based on the expression of 17 IFN-regulated genes (IRGs) in whole blood from 59 IgAN patients in a cross-sectional study, of which 34 patients followed longitudinally. Analysis of the IFN-score showed that there was a significant elevated IFN-score in the IgAN patients compared with healthy controls (n = 28, p = 9.80 × 10-3), and we observed an elevated IFN-score in the group with less tubular atrophy/interstitial fibrosis (p = 1.07 × 10-2) and with a lower proportion of mesangial hypercellularity (p = 1.23 × 10-2). In the longitudinal analysis, Cox regression analysis revealed that a higher IFN level was associated with a better renal outcome in IgAN after adjustments for gender and age (hazard ratio, 0.90; 95 % confidence interval, 0.81 to 0.97; p = 4.20 × 10-2). In conclusion, our finding suggested that IFN score may represent a novel type of biomarker in IgAN, which requires further exploration on its mechanism and therapeutic targeting.

Translational Control of Alphavirus-Host Interactions: Implications in Viral Evolution, Tropism and Antiviral Response.

Alphaviruses can replicate in arthropods and in many vertebrate species including humankind, but only in vertebrate cells do infections with these viruses result in a strong inhibition of host translation and transcription. Translation shutoff by alphaviruses is a multifactorial process that involves both host- and virus-induced mechanisms, and some of them are not completely understood. Alphavirus genomes contain cis-acting elements (RNA structures and dinucleotide composition) and encode protein activities that promote the translational and transcriptional resistance to type I IFN-induced antiviral effectors. Among them, IFIT1, ZAP and PKR have played a relevant role in alphavirus evolution, since they have promoted the emergence of multiple viral evasion mechanisms at the translational level. In this review, we will discuss how the adaptations of alphaviruses to vertebrate hosts likely involved the acquisition of new features in viral mRNAs and proteins to overcome the effect of type I IFN.

The tumor cell-intrinsic cGAS-STING pathway is associated with the high density of CD8+ T cells after chemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: Chemotherapy has the potential to induce CD8+ T-cell infiltration in the tumor microenvironment (TME) and activate the anti-tumor immune response in several cancers including esophageal squamous cell carcinoma (ESCC). The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been known as a critical component for regulating immune cell activation in the TME. However, its effect on the infiltration of immune cells induced by chemotherapy in the ESCC TME has not been investigated. METHODS: We examined the effect of the tumor-cell intrinsic cGAS-STING pathway on the infiltration of CD8+ T cells induced by chemotherapy in ESCC using ESCC cell lines and surgically resected ESCC specimens from patients who received neoadjuvant chemotherapy (NAC). RESULTS: We found that chemotherapeutic agents, including 5-fluorouracil (5-FU) and cisplatin (CDDP), activated the cGAS-STING pathway, consequently inducing the expression of type I interferon and T-cell-attracting chemokines in ESCC cells. Moreover, the tumor cell-intrinsic expression of cGAS-STING was significantly and positively associated with the density of CD8+ T cells in ESCC after NAC. However, the tumor cell-intrinsic expression of cGAS-STING did not significantly impact clinical outcomes in patients with ESCC after NAC. CONCLUSION: Our findings suggest that the tumor cell-intrinsic cGAS-STING pathway might contribute to chemotherapy-induced immune cell activation in the ESCC TME.

Type I interferon pathway genetic variants in severe COVID-19.

Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2. According to the World Health Organization (WHO), there have been over 760 million reported cases and over 6 million deaths caused by this disease worldwide. The severity of COVID-19 is based on symptoms presented by the patient and is divided as asymptomatic, mild, moderate, severe, and critical. The manifestations are interconnected with genetic variations. The innate immunity is the quickest response mechanism of an organism against viruses. Type I interferon pathway plays a key role in antiviral responses due to viral replication inhibition in infected cells and adaptive immunity stimulation induced by interferon molecules. Thus, variants in type I interferon pathway's genes are being studied in different COVID-19 manifestations. This review summarizes the role of variants in type I interferon pathway's genes on prognosis and severity progression of COVID-19.

Lumpy skin disease virus ORF127 protein suppresses type I interferon responses by inhibiting K63-linked ubiquitination of tank binding kinase 1.

Lumpy skin disease (LSD) is a severe animal infectious disease caused by lumpy skin disease virus (LSDV), inducing extensive nodules on the cattle mucosa or the scarfskin. LSDV genome encodes multiple proteins to evade host innate immune response. However, the underlying molecular mechanisms are poorly understood. In this study, we found that LSDV could suppress the expression of IFN-ß and interferon-stimulated genes (ISGs) in MDBK cells during the early stage of infection. Subsequently, an unbiased screen was performed to screen the LSDV genes with inhibitory effects on the type I interferon (IFN-I) production. ORF127 protein was identified as one of the strongest inhibitory effectors on the expression of IFN-ß and ISGs, meanwhile, the 1-43 aa of N-terminal of ORF127 played a vital role in suppressing the expression of IFN-ß. Overexpression of ORF127 could significantly promote LSDV replication through inhibiting the production of IFN-ß and ISGs in MDBK cells. Mechanism study showed that ORF127 specifically interacted with TBK1 and decreased the K63-linked polyubiquitination of TBK1 which suppressed the phosphorylation of TBK1 and ultimately decreased the production of IFN-ß. In addition, truncation mutation analysis indicated that the 1-43 aa of N-terminal of ORF127 protein was the key structural domain for its interaction with TBK1. In short, these results validated that ORF127 played a negative role in regulating IFN-ß expression through cGAS-STING signaling pathway. Taken together, this study clarified the molecular mechanism of ORF127 gene antagonizing IFN-I-mediated antiviral, which will helpfully provide new strategies for the treatment and prevention of LSD.

Sea perch (Lateolabrax japonicus) UBC9 augments RGNNV infection by hindering RLRs-interferon response.

Small ubiquitin-like modifier (SUMO) is a reversible post-translational modification that regulates various biological processes in eukaryotes. Ubiquitin-conjugating enzyme 9 (UBC9) is the sole E2-conjugating enzyme responsible for SUMOylation and plays an important role in essential cellular functions. Here, we cloned the UBC9 gene from sea perch (Lateolabrax japonicus) (LjUBC9) and investigated its role in regulating the IFN response during red-spotted grouper nervous necrosis virus (RGNNV) infection. The LjUBC9 gene consisted of 477 base pairs and encoded a polypeptide of 158 amino acids with an active site cysteine residue and a UBCc domain. Phylogenetic analysis showed that LjUBC9 shared the closest evolutionary relationship with UBC9 from Paralichthys olivaceus. Tissue expression profile analysis demonstrated that LjUBC9 was significantly increased in multiple tissues of sea perch following RGNNV infection. Further experiments showed that overexpression of LjUBC9 significantly increased the mRNA and protein levels of RGNNV capsid protein in LJB cells infected with RGNNV, nevertheless knockdown of LjUBC9 had the opposite effect, suggesting that LjUBC9 exerted a pro-viral effect during RGNNV infection. More importantly, we found that the 93rd cysteine is crucial for its pro-viral effect. Additionally, dual luciferase assays revealed that LjUBC9 prominently attenuated the promoter activities of sea perch type Ⅰ interferon (IFN) in RGNNV-infected cells, and overexpression of LjUBC9 markedly suppressed the transcription of key genes associated with RLRs-IFN pathway. In summary, these findings elucidate that LjUBC9 impairs the RLRs-IFN response, resulting in enhanced RGNNV infection.

Large overlap in neutrophil transcriptome between lupus and COVID-19 with limited lupus-specific gene expression.

OBJECTIVES: To illuminate the poorly understood aetiology of SLE by comparing the gene expression profile of SLE neutrophils with that of neutrophils from patients infected by SARS-CoV-2, a disease (COVID-19) with well-defined antigens and a similar type I interferon response. METHODS: RNA sequencing of neutrophils from patients with SLE (n=15) and healthy controls (n=12) was analysed for differential gene expression and modulated pathways. The same analyses were performed on a similar neutrophil dataset from patients with SARS-CoV-2 infection (n=30) and healthy controls (n=8). Next, we carried out comparative analyses to identify common and unique transcriptional changes between the two disease contexts, emphasising genes regulated in opposite directions. RESULTS: We identified 372 differentially expressed genes in SLE neutrophils compared with healthy donor neutrophils (≥2 fold, p<0.05), 181 of which were concordant with transcriptional changes in SARS-CoV-2-infected individuals compared with their respective healthy controls. In contrast, 118 genes demonstrated statistically significant alterations exclusive to SLE, including 28 genes that were differentially expressed in opposite directions in the two diseases. CONCLUSIONS: The substantial overlap between neutrophil responses in SLE and COVID-19 suggests that the unknown cause of SLE is functionally similar to a viral infection and drives a similar immune activation and type I interferon response. Conversely, the genes regulated in the opposite direction represent responses unique to SLE. These include tyrosylprotein sulfotransferase-1 and nucleic acid deaminases of the APOBEC family, which can catalyse cytosine-to-uridine editing of both RNA and DNA, and other RNA-modifying enzymes.

Role of micronucleus-activated cGAS-STING signaling in antitumor immunity. / å¾®æ ¸æ¿€æ´»cGAS-STINGä¿¡å·é€šè·¯çš„æœºåˆ¶åŠå ¶è‚¿ç˜¤å ç–«åŠŸèƒ½.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling is a significant component of the innate immune system and functions as a vital sentinel mechanism to monitor cellular and tissue aberrations in microbial invasion and organ injury. cGAS, a cytosolic DNA sensor, is specialized in recognizing abnormally localized cytoplasmic double-stranded DNA (dsDNA) and catalyzes the formation of a second messenger cyclic-GMP-AMP (cGAMP), which initiates a cascade of type Ⅰ interferon and inflammatory responses mediated by STING. Micronucleus, a byproduct of chromosomal missegregation during anaphase, is also a significant contributor to cytoplasmic dsDNA. These unstable subcellular structures are susceptible to irreversible nuclear envelope rupture, exposing genomic dsDNA to the cytoplasm, which potently recruits cGAS and activates STING-mediated innate immune signaling and its downstream activities, including type Ⅰ interferon and classical nuclear factor-κB (NF-κB) signaling pathways lead to senescence, apoptosis, autophagy activating anti-cancer immunity or directly killing tumor cells. However, sustained STING activation-induced endoplasmic reticulum stress, activated chronic type Ⅰ interferon and nonclassical NF-κB signaling pathways remodel immunosuppressive tumor microenvironment, leading to immune evasion and facilitating tumor metastasis. Therefore, activated cGAS-STING signaling plays a dual role of suppressing or facilitating tumor growth in tumorigenesis and therapy. This review elaborates on research advances in mechanisms of micronucleus inducing activation of cGAS-STING signaling and its implications in tumorigenesis and therapeutic strategies of malignant tumors.

Distinct antiviral activities of IFNφ1 and IFNφ4 in zebrafish.

Interferons (IFNs) are a group of secreted cytokines that play a crucial role in antiviral immunity. Type I IFNs display functional disparities. In teleosts, type I IFNs are categorized into two subgroups containing one or two pairs of disulfide bonds. However, their functional differences have not been fully elucidated. In this study, we comparatively characterized the antiviral activities of zebrafish IFNφ1 and IFNφ4 belonging to the group I type I IFNs. It was found that ifnφ1 and ifnφ4 were differentially modulated during viral infection. Although both IFNφ1 and IFNφ4 activated JAK-STAT signaling pathway via CRFB1/CRFB5 receptor complex, IFNφ4 was less potent in inducing phosphorylation of STAT1a, STAT1b and STAT2 and the expression of antiviral genes than IFNφ1, thereby conferring weaker antiviral resistance of target cells. Taken together, our results provide insights into the functional divergence of type I IFNs in lower vertebrates.