Interferon-stimulated Genes Research Articles

KSHV hijacks the antiviral kinase IKKε to initiate lytic replication.

IKKε is a traditional antiviral kinase known for positively regulating the production of type I interferon (IFN) and the expression of IFN-stimulated genes (ISGs) during various virus infections. However, through an inhibitor screen targeting cellular kinases, we found that IKKε plays a crucial role in the lytic replication of Kaposi's sarcoma-associated herpesvirus (KSHV). Mechanistically, during KSHV lytic replication, IKKε undergoes significant SUMOylation at both Lys321 and Lys549 by the viral SUMO E3 ligase ORF45. This SUMOylation event leads to the association of IKKε with PML, resulting in the disruption of PML nuclear bodies (PML NBs) and subsequent increase in lytic replication of KSHV. Notably, IKKε does not affect the total expression level of PML but facilitates the translocation of PML from the nucleus to the cytoplasm during KSHV lytic replication. Further experiments utilizing mutations on the SUMOylation sites of IKKε or inhibiting IKKε using BAY-985 showed that these actions no longer impact PML NBs and completely suppress the lytic replication of KSHV. These findings not only emphasize the essential role of IKKε in the life cycle of KSHV but also illustrate how KSHV exploits IKKε through SUMOylation modification to enhance its own replication process.

Endothelial STING-JAK1 interaction promotes tumor vasculature normalization and antitumor immunity.

Stimulator of interferon genes (STING) agonists have been developed and tested in clinical trials for their antitumor activity. However, the specific cell population(s) responsible for such STING activation-induced antitumor immunity have not been completely understood. In this study, we demonstrated that endothelial STING expression was critical for STING agonist-induced antitumor activity. STING activation in endothelium promoted vessel normalization and CD8+ T cell infiltration - which required type I IFN (IFN-I) signaling- but not IFN-γ or CD4+ T cells. Rather than an upstream adaptor for inducing IFN-I signaling, STING acted downstream of interferon-α/β receptor (IFNAR) in endothelium for the JAK1-STAT signaling activation. Mechanistically, IFN-I stimulation induced JAK1-STING interaction and promoted JAK1 phosphorylation, which involved STING palmitoylation at the Cysteine 91 site but not its C-terminal tail (CTT) domain. Endothelial STING and JAK1 expression was significantly associated with immune cell infiltration in patients with cancer, and STING palmitoylation level correlated positively with CD8+ T cell infiltration around STING-positive blood vessels in tumor tissues from patients with melanoma. In summary, our findings uncover a previously unrecognized function of STING in regulating JAK1/STAT activation downstream of IFN-I stimulation and provide a new insight for future design and clinical application of STING agonists for cancer therapy.

Open-label, phase Ia study of STING agonist BI 1703880 plus ezabenlimab for patients with advanced solid tumors.

BI 1703880, a novel STimulator of INterferon Genes (STING) agonist, has demonstrated preclinical antitumor activity. As STING activation can upregulate programmed death ligand 1 and human leukocyte antigen in tumor cells, a combination of BI 1703880 and an anti-programmed cell death protein 1-antibody, such as ezabenlimab, may improve efficacy. This first-in-human phase Ia study (NCT05471856) is evaluating BI 1703880 plus ezabenlimab in patients with advanced solid tumors. The study utilizes an innovative lead-in design; all patients receive BI 1703880 monotherapy in Cycle 1 and combination therapy from Cycle 2. The primary endpoint is dose-limiting toxicities during the maximum tolerated dose evaluation period. Results will inform the future development of BI 1703880 for treatment of metastatic or recurrent malignancies.Clinical Trial number: NCT05471856.

Activation of the cGAS-sting Pathway Mediated by Nanocomplexes for Tumor Therapy.

cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway is an natural immune response signaling pathway in the human body that is essential for sensing abnormal DNA aggregation in the cell. When the cGAS protein senses abnormal or damaged DNA, it forms a second messenger called cyclic dinucleotide (cGAMP). The cycled dinucleotide will activate the downstream STING protein, thereby inducing the expression of inflammatory cytokines such as type I interferon, which binds to receptors on its own cell membrane and ultimately initiates multiple immune response pathways. This signaling pathway plays an important immune role in antimicrobial and antitumor functions, etc. so the development of drugs targeting this signaling pathway has important clinical application value. In recent years nanocomplexes based cGAS-STING signaling pathway activation and inhibition treatments have been gradually developed. In this review, on the basis of elaborating the main activation mechanism of the cGAS-STING pathway, we further introduced the nanocomplexes that effectively activate the cGAS-STING pathway, focusing on the composition, types and applications of the nanocomplexes. In addition, we discussed the key challenges and future research directions of the way that stimulating the cGAS-STING signaling pathway in the form of nanocomplexes to activate immuno-tumor therapy. Our work aims to provide a better understanding of the progress of nanotherapeutics in the cGAS-STING pathway, providing a promising anti-tumor therapeutic strategy.

Acute inflammation induces acute megakaryopoiesis with impaired platelet production during fetal hematopoiesis.

Hematopoietic development is tightly regulated by various factors. The role of RNA m6A modification during fetal hematopoiesis, particularly in megakaryopoiesis, remains unclear. Here, we demonstrate that loss of m6A methyltransferase METTL3 induces formation of double-stranded RNAs (dsRNAs) and activates acute inflammation during fetal hematopoiesis. This dsRNA-mediated inflammation leads to acute megakaryopoiesis, which facilitates the generation of megakaryocyte progenitors (MkP) but disrupts megakaryocyte maturation and platelet production. The inflammation and immune response activate the phosphorylation of STAT1 and IRF3, and upregulate downstream interferon-stimulated genes (ISGs). Inflammation inhibits the proliferation rate of hematopoietic progenitors and further skews the cell fate determination toward megakaryocytes rather than erythroid from megakaryocyte-erythroid progenitors (MEPs). Transcriptional-wide gene expression analysis identifies IGF1 as a major factor whose reduction is responsible for the inhibition of megakaryopoiesis and thrombopoiesis. Restoration of IGF1 with METTL3-deficient hematopoietic cells significantly increase megakaryocyte maturation. In summary, we elucidate that the loss of RNA m6A modification-induced acute inflammation activates acute megakaryopoiesis but impairs its final maturation through the inhibition of IGF1 expression during fetal hematopoiesis.

Targeting MXD1 sensitises pancreatic cancer to trametinib

BackgroundThe resistance of pancreatic ductal adenocarcinoma (PDAC) to trametinib therapy limits its clinical use. However, the molecular mechanisms underlying trametinib resistance in PDAC remain unclear.ObjectiveWe aimed to illustrate the mechanisms...

Acute Severe Hypoxia Decreases Mitochondrial Chain Complex II Respiration in Human Peripheral Blood Mononuclear Cells

Peripheral blood mononuclear cells’ (PBMCs) mitochondrial respiration is impaired and likely involved in myocardial injury and heart failure pathophysiology, but its response to acute and severe hypoxia, often associated with such diseases, is largely unknown in humans. We therefore determined the effects of acute hypoxia on PBMC mitochondrial respiration and ROS production in healthy volunteers exposed to controlled oxygen reduction, achieving an inspired oxygen fraction of 10.5%. We also investigated potential relationships with gene expression of key biomarkers of hypoxia, succinate and inflammation, as hypoxia and inflammation share common mechanisms involved in cardiovascular disease. Unlike global mitochondrial respiration, hypoxemia with a spO2 ≤ 80% significantly reduced PBMC complex II respiration (from 6.5 ± 1.2 to 3.1 ± 0.5 pmol/s/106 cell, p = 0.04). Complex II activity correlated positively with spO2 (r = 0.63, p = 0.02) and inversely correlated with the succinate receptor SUCNR1 (r = −0.68), the alpha-subunit of the hypoxia-inducible factor (HIF-1α, r = −0.61), the chemokine ligand-9 (r = −0.68) and interferon-stimulated gene 15 (r = −0.75). In conclusion, severe hypoxia specifically impairs complex II respiration in association with succinate, inflammation and HIF-1α pathway interactions in human PBMCs. These results support further studies investigating whether modulation of complex II activity might modify the inflammatory and metabolic alterations observed in heart failure.

Agonists Targeting the cGAS-STING Signaling Pathway and Their Applications in Cancer Therapy

The cyclic GMP-AMP synthase (cGAS) serves as a pivotal component of the immune system, playing a crucial role in regulating the innate immune response elicited by both exogenous and endogenous DNA. This enzyme recognizes the aberrant presence of DNA in the cytoplasm, subsequently activating the signaling pathway mediated by the stimulator of interferon genes (STING) and thereby fulfilling a critical role in immune response mechanisms. This review delineates the mechanisms of the cGAS-STING pathway and elucidates the small-molecule agonists targeting STING, along with their combined applications in various tumor treatment strategies. The aim of this review is to provide a valuable reference framework and insights for ongoing research in related fields.

Decreased STING predicts adverse efficacy in bortezomib regimens and poor survival in multiple myeloma

PurposeSTING (stimulator of interferon genes) is involved in viral and bacterial defense through interferon pathway and innate immunity. Increased susceptibility to infection is a common manifestation of multiple myeloma (MM). Thus, we aimed to explore the clinical significance and possible mechanism of STING in MM.Materials and methodsImmunohistochemistry and qPCR were used to detect STING expression in the bone marrow of MM patients, and flow cytometry was used to detect the amount of intracellular STING. All data were analyzed with clinical characteristics.ResultsSTING expression was remarkably reduced in MM tissues compared to normal tissues and was not associated with stage. Multivariate analysis identified STING as an independent prognostic factor in MM patients (P = 0.001). In the bortezomib-containing regimens, patients with low STING expression were more difficult to achieve remission. A model incorporating STING and m-SMART significantly improved the predictive accuracy of overall survival in bortezomib regimens (AUC, 0.511 to 0.630, P = 0.044). Bortezomib efficacy has been reported to correlate with activated immunity, but the low expression group manifested as immune apathy. Although baseline characteristics showed intergroup differences in infection, the low expression group had an increased proportion of bacterial infections (1.7-fold) and a prolonged duration of antibiotic/antifungal medication (3.55 additional days); these patients were accompanied by a decreased neutrophil-to-lymphocyte ratio (NLR) and rarely activated neutrophils and leukocytes. The intracellular STING ratio was also defective in neutrophil-dominated leukocytes.ConclusionOur study revealed that STING had a strong association with bortezomib and could serve as a potential target for immunotherapy in multiple myeloma.

Grass carp reovirus VP4 manipulates TOLLIP to degrade STING for inhibition of IFN production.

Upon virus invasion, fish cells employ a multitude of strategies to defend against infection. Consequently, viruses have evolved a plethora of tactics to evade host antiviral mechanisms. To date, fewer studies have been conducted on the immune evasion mechanism of grass carp reovirus (GCRV). In this study, we demonstrate that VP4 of GCRV-873 inhibits interferon expression by interacting with stimulator of IFN gene and degrading it in an autophagy-lysosome-dependent manner through the manipulation of the selective autophagy receptor toll-interacting protein. The findings of this study contribute to our understanding of the novel evasion mechanisms of GCRV and widen our knowledge of the virus-host interactions in lower vertebrates.

ZNFX1 functions as a master regulator of epigenetically induced pathogen mimicry and inflammasome signaling in cancer.

DNA methyltransferase and poly (ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon genes (STING)-dependent pathogen mimicry response (PMR) in ovarian and other cancers. Here, we showed that combining DNMTis and PARPis upregulates expression of the nucleic-acid sensor NFX1-type zinc finger-containing 1 protein (ZNFX1). ZNFX1 mediated induction of PMR in mitochondria, serving as a gateway for STING-dependent interferon/inflammasome signaling. Loss of ZNFX1 in ovarian cancer cells promoted proliferation and spheroid formation in vitro and tumor growth in vivo. In patient ovarian cancer databases, expression of ZNFX1 was elevated in advanced stage disease, and ZNFX1 expression alone significantly correlated with an increase in overall survival in a phase 3 trial for therapy-resistant ovarian cancer patients receiving bevacizumab in combination with chemotherapy. RNA-sequencing revealed an association between inflammasome signaling through ZNFX1 and abnormal vasculogenesis. Together, this study identified that ZNFX1 as a tumor suppressor that controls PMR signaling through mitochondria and may serve as a biomarker to facilitate personalized therapy in ovarian cancer patients.

Design, Synthesis, and Biological Assessment of Novel Aminobenzidazole Agonists Targeting the Stimulator of Interferon Genes (STING) Receptor Signaling Pathway for Oncology Immunotherapy.

The activation of the STING-mediated signaling pathway leads to the secretion of type I interferon (IFN) and the activation of tumor-specific T cells. STING, a pattern recognition receptor located on the endoplasmic reticulum membrane of immune cells, binds with endogenous cyclic dinucleotides. STING undergoes phosphorylation, triggering the STING-TBK1-IRF3 pathway and NF-κB pathway, resulting in the release of IFN-β and other pro-inflammatory cytokines, ultimately enhancing the activation of tumor-specific T cells. This mechanism serves to complement the limitations of immune checkpoint inhibitors and enhances the efficiency of the immune response. This study selected benzimidazole compounds GSK and SR-717, which exhibit promising potential as patented medicines, as our lead compounds. Aiming to address the challenges associated with the short half-life of benzimidazole compounds and the limited molecular activity of SR-717, we designed and synthesized a series of STING agonists (compounds 6~29). The compound 17 showed excellent agonistic activity on hSTING protein in vitro. The cytotoxicity tests of all the synthesized compounds were performed in vitro. Performed in vivo pharmacokinetic studies on the most promising compounds and conducted molecular docking analyses.

The pseudorabies virus UL13 protein kinase triggers phosphorylation of the RNA demethylase FTO, which is associated with FTO-dependent suppression of interferon-stimulated gene expression.

Alpha-ketoglutarate-dependent dioxygenase, also known as fat mass and obesity-associated protein (FTO), is an RNA demethylase that mediates the demethylation of N6,2-O-dimethyladenosine (m6Am) and N6-methyladenosine (m6A). Both m6Am and m6A are prevalent modifications in mRNA and affect different aspects of transcript biology, including splicing, nuclear export, translation efficiency, and degradation. The role of FTO during (herpes) virus infection remains largely unexplored. In this study, we show that the UL13 protein kinase of the alphaherpesvirus pseudorabies virus (PRV) triggers phosphorylation of FTO. In primary epithelial cells, depletion of FTO leads to increased expression of antiviral interferon-stimulated genes (ISGs) and UL13 triggers FTO-dependent suppression of ISG expression. Although PRV infection suppresses m6Am levels in host small nuclear RNA, this is independent of UL13. The current data highlight FTO as an important regulator of antiviral ISG expression and suggest that UL13-mediated phosphorylation of FTO may serve as a previously unrecognized viral strategy to suppress the antiviral interferon response.IMPORTANCERNA modification pathways play important roles in diverse cellular processes and virus life cycles. Although previous studies have demonstrated that alphaherpesviruses can substantially influence cellular RNA modifications, such as m6A, the impact on the m6Am epitranscriptome machinery remains largely unexplored. The present work reports that the UL13 protein kinase of pseudorabies virus (PRV), an alphaherpesvirus, mediates phosphorylation of the m6Am/m6A eraser FTO and that this correlates with a UL13- and FTO-dependent suppression of antiviral interferon-stimulated gene (ISG) expression. Furthermore, PRV infection leads to a pronounced reduction in m6Am levels in host snRNA and also induces phosphorylation of the m6Am writer PCIF1. These data highlight FTO as an important regulator of ISG expression and reveal that viral manipulation of FTO, such as UL13-induced phosphorylation of FTO, may serve as a previously unrecognized interferon evasion strategy.

BEND6 promotes RNA viruses' replication by inhibiting innate immune responses.

Innate immunity serves as a crucial defense mechanism against invading pathogens, yet its negative regulatory network remains under explored. In this study, we identify BEN domain-containing protein 6 (BEND6) as a novel negative regulator of innate immunity through a genome-scale CRISPR knockout screen for host factors essential for viral replication. We show that BEND6 exhibits characteristics of an interferon-stimulated gene (ISG), with its mRNA and protein levels upregulated by RNA virus-induced IFN-β. BEND6 targets IRF3 and inhibits its recruitment by TBK1, thus preventing IRF3 phosphorylation and dimerization. Additionally, BEND6 directly binds to ISRE, thereby hindering the DNA binding activity of IRF3 and blocking the subsequent activation of IFN-β transcription. Taken together, our study reveals the mechanism of BEND6 in promoting the replication of various RNA viruses and provides a potential therapeutic target for RNA virus infection.

Laminaran potentiates cGAS-STING signaling to enhance antiviral responses.

Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling pathway, an essential element in the innate antiviral immune responses, has emerged as a key component of innate immune system to modulate type I IFNs production and response by recognizing both exogenous and endogenous DNA. Although some cGAS-STING signaling small molecule agonists have been developed, there are few natural polysaccharides reported to activate cGAS-STING signaling for the treatment of infectious diseases. Here, we reported that Laminaran, a low molecular weight β-glucan storage polysaccharide present in brown algae, potentiates cGAS-STING signaling to promote type I IFNs production and antiviral response. Laminaran enhanced cGAS-STING signaling mediated type I IFNs production and response both in human and murine cells upon HSV-1 infection or DNA mimics stimulation. Importantly, we found that Laminaran markedly inhibited Herpes simplex virus-1 (HSV-1) induced death and inflammatory responses and increased the induction of type I IFNs in C57BL/6J mice. Mechanistically, we found Laminaran inhibited autophagy and suppressed STING autophagic degradation to positively regulate cGAS-STING signaling response. Taken together, we uncovered the function of Laminaran in DNA triggered innate immunity by enhancing cGAS-STING signaling response. Laminaran might be a potential therapeutic candidate for viral infectious diseases.

Hovenia dulcis Thunb. Honey Exerts Antiviral Effect Against Influenza A Virus Infection Through Mitochondrial Stress-Mediated Enhancement of Innate Immunity

To combat influenza A virus (IAV) infection, it is vital to develop effective therapeutic strategies, including immunomodulators. In this study, we examined the antiviral effects of Hovenia dulcis Thunb. honey (HDH) against IAV using RAW 264.7 cells. HDH treatment significantly reduced IAV infection and viral protein expression. Moreover, it enhanced the production of interferon (IFN)-β, activated the innate immune response through the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, and upregulated IFN signaling through signal transducer and activator of transcription (STAT)1/2 phosphorylation and interferon-stimulated gene (ISG) expression. In addition, HDH decreased IAV-induced intracellular and mitochondrial reactive oxygen species (ROS) production by upregulating the expression of antioxidant proteins, such as Sirt3 and SOD2. The results suggest that HDH is a potential therapeutic agent inhibiting viral replication and boosting host antiviral immunity.

Dendrimer-Mediated Generation of a Metal-Phenolic Network for Antibody Delivery to Elicit Improved Tumor Chemo/Chemodynamic/Immune Therapy.

To simplify the composition and improve the efficacy of metal-phenolic network (MPN)-based nanomedicine, herein, we designed an MPN platform to deliver programmed death ligand-1 (PD-L1) antibody (anti-PD-L1) for combined tumor chemo/chemodynamic/immune therapy. Here, generation 5 poly(amidoamine) dendrimers conjugated with gossypol (Gos) through boronic ester bonds were used as a synthetic polyphenol to coordinate Mn2+, and then complexed with anti-PD-L1 to obtain the nanocomplexes (for short, DPGMA). The prepared DPGMA exhibited good water dispersibility with a hydrodynamic size of 166.3 nm and tumor-microenvironment-responsive drug release behavior. The integration of Gos and Mn2+ within the DPGMA resulted in significant tumor inhibition and immunogenic cell death activation through Gos-mediated chemotherapy and Mn2+-catalyzed chemodynamic therapy, respectively, thereby leading to significant dendritic cell maturation due to the role of Mn2+ played to mediate the activation of the stimulator of interferon genes (STING) pathway. Moreover, the complexed anti-PD-L1 promoted the recognition and uptake of nanocomplexes by PD-L1-overexpressed tumors through antibody targeting, thereby achieving combinational chemo/chemodynamic/immune therapy in a mouse melanoma model, where the immunotherapy modes combined three parts of activation via chemotherapy/CDT-mediated ICD, Mn2+-mediated STING activation, and antibody-mediated immune checkpoint blockade. With the Mn2+-endowed r1 relaxivity (1.38 mM-1 s-1), the DPGMA nanocomplexes can also be used for tumor MR imaging. The designed dendrimer-mediated MPN platform may be developed as an advanced nanomedicine to tackle other cancer types.

Using cationic liposomes as carriers for long dsRNA to trigger an antiviral response in rainbow trout cell lines.

Long dsRNA induces the expression of type I interferons (IFNs) and IFN-stimulated genes (ISGs) to establish an antiviral state. When induced prophylactically, this antiviral state can reduce the severity and mortality of viral infections. One of the limiting factors in delivering dsRNA in animal models is the lack of an effective carrier that protects the dsRNA from degradation in the extracellular space. In this study, commercially available cationic liposomes composed of stearylamine, L-α-phosphatidylcholine, and cholesterol were analyzed for their ability to encapsulate and deliver a 621-bp dsRNA sequence. This encapsulated dsRNA was delivered to two Oncorhynchus mykiss cell lines, RTG-2 and RTgill-W1, to activate the IFN pathway and reduce chum salmon reovirus (CSV) infection. EMSA analysis revealed that the liposomes effectively encapsulated 55 and 800µg/mL doses of dsRNA, remained stable when stored at 4°C and - 20°C, and protected the encapsulated dsRNA from degradation by RNase III. Cell viability assays determined that liposomes loaded with dsRNA were highly cytotoxic after 24h of exposure. A shorter exposure of 2h resulted in reduced cytotoxicity and enhanced expression of the ISG Mx1 in both dsRNA alone and dsRNA-liposome-treated cells; however, the elevated Mx1 induction was not sufficient in the dsRNA-liposome treatment group to provide protection against viral infection. Meanwhile, the unencapsulated dsRNA significantly reduced the CSV titer and amount of syncytia formation. Thus, while dsRNA represents an important immune modulator in fish cells, this liposome formulation is too toxic for antiviral applications.

Stimulator of Interferon Genes Signal in Lung Cancer Regulates Differentiation of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment Via the Interferon Regulatory Factor 3/NF-κB Pathway.

Background: This study was designed to explore the action mechanism of stimulator of interferon genes (STING) on the differentiation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment of lung cancer. Methods: Bioinformatics analysis yielded a potential pathway for STING to regulate MDSC differentiation, the interferon regulatory factor 3 (IRF3)/NF-κB axis. The transfection efficiency of STING overexpression plasmid and small interfering RNA against IRF3 (siIRF3) was examined by quantitative real-time polymerase chain reaction (qRT-PCR). After transfection, A9 cells were co-cultured with extracted bone marrow cells (BMCs). MDSC differentiation, protein expression of the IRF3/NF-κB pathway, and changes in nuclear translocation of NF-κB were analyzed by flow cytometry, Western blot, and immunofluorescence staining experiments. A transplanted tumor mouse model was used for invivo experiments. After cyclic diadenyl monophosphate (CDA; STING agonist) treatment, changes in MDSC differentiation and protein expression of the IRF3/NF-κB axis in transplanted tumors were verified by immunohistochemical staining, qRT-PCR, and Western blot. Results: Coculture of A9 cells and BMCs promoted MDSC differentiation, inhibited activation of IRF3/NF-κB signal in A9 cells, and boosted nuclear translocation of NF-κB. However, after the upregulation of STING, IRF3/NF-κB signal was activated, while MDSC differentiation and nuclear translocation of NF-κB were inhibited. SiIRF3 reversed the effects of STING overexpression. In vivo, CDA dampened MDSC differentiation and promoted protein expression of the IRF3/NF-κB axis. Conclusion: STING signal in lung cancer cells inhibits MDSC differentiation through activation of the IRF3/NF-κB pathway.

An interferon-stimulated long non-coding RNA USP30-AS1 as an immune modulator in influenza A virus infection.

Long non-coding RNAs (lncRNAs) are essential components of innate immunity, maintaining the functionality of immune systems that control virus infection. However, how lncRNAs engage immune responses during influenza A virus (IAV) infection remains unclear. Here, we show that lncRNA USP30-AS1 is up-regulated by infection of multiple different IAV subtypes and is required for tuning inflammatory and antiviral response in IAV infection. Genetically inactivation of USP30-AS1 enhances viral protein synthesis and viral growth. USP30-AS1 is an interferon-stimulated gene, and the induction of USP30-AS1 can be achieved by JAK-STAT mediated signaling activation. The immune regulation of USP30-AS1 is independent of its proximal protein-coding gene USP30. In IAV infection, deletion of USP30-AS1 unleashes high systemic inflammatory responses involving a broad range of pro-inflammatory factors, suggesting USP30-AS1 as a critical modulator of immune responses in IAV infection. Furthermore, we established a database providing well-annotated host gene expression profiles IAV infection or immune stimulation.