siRNA enhances DNA-mediated interferon lambda-1 response through crosstalk between RIG-I and IFI16 signalling pathway

In addition to silencing specific genes, small interfering RNA (siRNA) transfection is also associated with the non-specific induction of inflammatory cytokines and type I interferon. Those so-called “off-target” effects have considerable implications for the interpretation of in vitro studies and clinical application of siRNA. The present study attempted to develop a better understanding of the mechanism involved in these off target effects. Synthesized siRNA significantly enhances DNA-mediated interferon lambda-1 response (IFN-λ1/IL-29), a newly characterized antiviral interferon in non-immune or primary immune cells. This enhancement was most pronounced by double-stranded siRNA with at least a 2-nucleotide overhang at one 3′ terminus in a dose-dependent manner, while the presence of DNA was indispensable. A pull-down assay using biotinylated siRNA- or DNA-conjugated beads indicated that retinoic acid-inducible gene I (RIG-I) and interferon gamma-inducible protein 16 (IFI16) were involved in the sensing of siRNA and DNA, respectively. Co-immunoprecipitation analysis further revealed that RIG-I and IFI16 formed a complex via siRNA, and the dissociation of IFI16 from this complex in the presence of DNA activated the downstream STING-TBK1-IRF3 (stimulator of interferon genes – tank-binding kinase 1 – interferon regulatory factor 3) pathway, shedding light on a new physiological signalling pathway to activate innate immunity. Collectively, these findings may provide rational information for siRNA-induced innate immunity, with important implications for developing siRNA-based reagents to control human diseases.

• Publication year

  2013

• Venue

  Nucleic Acids Research

• Publication date

  2013-09-18

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1093/nar/gkt844PMID 24049081PMCID 3874163
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Nucleic Acids Research

  2015cited by this paper
• Interleukin-27 Is a Potent Inhibitor of cis HIV-1 Replication in Monocyte-Derived Dendritic Cells via a Type I Interferon-Independent Pathway

  2013cited by this paper
• STING Specifies IRF3 Phosphorylation by TBK1 in the Cytosolic DNA Signaling Pathway

  2012cited by this paper
• STING-dependent signaling

  2011cited by this paper
• Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA.

  2011cited by this paper
• Cutting Edge: Ku70 Is a Novel Cytosolic DNA Sensor That Induces Type III Rather Than Type I IFN

  2011cited by this paper
• Rational design of immunostimulatory siRNAs.

  2010cited by this paper
• IFI16 is an innate immune sensor for intracellular DNA

  2010influential reference
• Lambda Interferon Inhibits Human Immunodeficiency Virus Type 1 Infection of Macrophages

  2009cited by this paper
• Histone H2A.Z cooperates with RNAi and heterochromatin factors to suppress antisense RNAs

  2009cited by this paper
• STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity

  2009cited by this paper
• RNA recognition and signal transduction by RIG‐I‐like receptors

  2009cited by this paper
• Recognition of 5' triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus.

  2009cited by this paper
• Short-hairpin RNAs delivered by lentiviral vector transduction trigger RIG-I-mediated IFN activation

  2009cited by this paper
• Small Interfering RNA Targeting M2 Gene Induces Effective and Long Term Inhibition of Influenza A Virus Replication

  2009cited by this paper
• Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response

  2009cited by this paper
• Noninfectious papilloma virus-like particles inhibit HIV-1 replication: implications for immune control of HIV-1 infection by IL-27.

  2007cited by this paper
• 5'-Triphosphate RNA Is the Ligand for RIG-I

  2006cited by this paper
• siRNA and isRNA: two edges of one sword.

  2006cited by this paper
• A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells

  2006cited by this paper
• Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA

  2005influential reference
• Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein that Activates NF-κB and IRF3

  2005cited by this paper
• Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7

  2005influential reference
• Activation of the mammalian immune system by siRNAs

  2005cited by this paper
• Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3.

  2005cited by this paper
• Induction of inflammatory cytokines and interferon responses by double-stranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization.

  2005cited by this paper
• Interferon induction by siRNAs and ssRNAs synthesized by phage polymerase

  2004cited by this paper
• Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs

  2004cited by this paper
• Small interfering RNA targeting Fas protects mice against renal ischemia-reperfusion injury.

  2004cited by this paper
• Principles: receptor theory in pharmacology.

  2004cited by this paper
• Small Interfering RNAs Mediate Sequence-Independent Gene Suppression and Induce Immune Activation by Signaling through Toll-Like Receptor 31

  2004cited by this paper
• Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8

  2004cited by this paper
• Recognition of single-stranded RNA viruses by Toll-like receptor 7.

  2004cited by this paper
• The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses

  2004cited by this paper
• Inhibition of influenza virus production in virus-infected mice by RNA interference.

  2004cited by this paper
• Gene silencing by systemic delivery of synthetic siRNAs in adult mice.

  2003cited by this paper
• IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex

  2003cited by this paper
• IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.

  2003cited by this paper
• Activation of the interferon system by short-interfering RNAs

  2003cited by this paper
• RNA interference targeting Fas protects mice from fulminant hepatitis

  2003cited by this paper
• Antisense-RNA regulation and RNA interference.

  2002cited by this paper
• Decoding the Patterns of Self and Nonself by the Innate Immune System

  2002cited by this paper
• Innate immune recognition.

  2002cited by this paper
• IL-28, IL-29 and their class II cytokine receptor IL-28R

  2002cited by this paper
• RNA interference--2001.

  2001cited by this paper
• Post-transcriptional gene silencing in plants.

  2001cited by this paper
• An overview of the immune system.

  2001cited by this paper
• Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3

  2001cited by this paper
• Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells

  2001cited by this paper
• Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans

  1998cited by this paper

• The ever-expanding role of IFI16 in the anti-viral innate immune response.

  2026cites this paper
• Manganese mediates antiviral effects by driving an ATM -TBK1 phosphorylation signaling pathway

  2025cites this paper
• Next-generation nanocarriers for therapeutic oligonucleotides: Precision targeting and stimuli-responsive cancer therapy.

  2025cites this paper
• Manganese mediates antiviral effects by driving an ATM -TBK1 phosphorylation signaling pathway

  2025cites this paper
• Catch me if you can: viral nucleic acids to host sensors

  2025cites this paper
• IGF2BP1 promotes multiple myeloma with chromosome 1q gain via increasing CDC5L expression in an m6A-dependent manner

  2024cites this paper
• New Insights into Nucleic Acid Sensor AIM2: The Potential Benefit in Targeted Therapy for Cancer.

  2024cites this paper
• Interleukin-27-induced HIV-resistant dendritic cells suppress reveres transcription following virus entry in an SPTBN1, Autophagy, and YB-1 independent manner

  2023cites this paper
• Interleukin-27-induced HIV-resistant dendritic cells suppress reveres transcription following virus entry in an SPTBN1, autophagy, and YB-1 independent manner

  2023cites this paper
• A newly-synthesized compound CP-07 alleviates microglia-mediated neuroinflammation and ischemic brain injury via inhibiting STAT3 phosphorylation

  2023cites this paper
• A DNA Pull-Down Assay with Diversity Forms of Competitor for Detecting or Evaluating Protein-DNA Interactions.

  2023cites this paper
• Non-targeting siRNA-mediated responses are associated with apoptosis in chemotherapy-induced senescent skin cancer cells.

  2022cites this paper
• Activation and Immune Regulation Mechanisms of PYHIN Family During Microbial Infection

  2022cites this paper
• Cytoplasmic‐translocated Ku70 senses intracellular DNA and mediates interferon‐lambda1 induction

  2021cites this paper
• IFI16 directly senses viral RNA and enhances RIG-I transcription and activation to restrict influenza virus infection

  2021cites this paper
• MicroRNA Profiles in Monocyte-Derived Macrophages Generated by Interleukin-27 and Human Serum: Identification of a Novel HIV-Inhibiting and Autophagy-Inducing MicroRNA

  2021cites this paper
• An in silico approach to design potential siRNA molecules of SARSCoV-2 Virus structural genes, a preliminary opinion for COVID-19 inhibition

  2020cites this paper
• Zika Virus-Induction of the Suppressor of Cytokine Signaling 1/3 Contributes to the Modulation of Viral Replication

  2020influential citation
• A pull-down assay using DNA/RNA-conjugated beads with a customized competition strategy: An effective approach to identify DNA/RNA binding proteins

  2020cites this paper
• Baculovirus Transduction in Mammalian Cells Is Affected by the Production of Type I and III Interferons, Which Is Mediated Mainly by the cGAS-STING Pathway

  2020cites this paper
• Profiles of MicroRNAs in Interleukin–27-Induced HIV-Resistant T Cells: Identification of a Novel Antiviral MicroRNA

  2020cites this paper
• siRNA containing a unique 5-nucleotide motif acts as a quencher of IFI16-mediated innate immune response

  2019cites this paper
• Strategies for improving the specificity of siRNAs for enhanced therapeutic potential

  2018cites this paper
• STING is an essential mediator of the Ku70-mediated production of IFN-λ1 in response to exogenous DNA

  2017cites this paper
• Crosstalk between Cytoplasmic RIG-I and STING Sensing Pathways.

  2017cites this paper
• Therapeutic potentials of short interfering RNAs

  2017cites this paper
• RNA Interference (RNAi)-Based Therapeutics: Delivering on the Promise?

  2016cites this paper
• Perspectives on RNA Interference in Immunopharmacology and Immunotherapy

  2016cites this paper
• Rearrangement of mitochondrial pyruvate dehydrogenase subunit dihydrolipoamide dehydrogenase protein–protein interactions by the MDM2 ligand nutlin‐3

  2016cites this paper
• Identifying long-range control elements of the BRCA1 promoter

  2015cites this paper
• Proapoptotic and Antiapoptotic Proteins of the Bcl-2 Family Regulate Sensitivity of Pancreatic Cancer Cells Toward Gemcitabine and T-Cell–mediated Cytotoxicity

  2015cites this paper
• Complicated, Critical and Elusive Role of IFN-λ

  2015cites this paper
• The unique regulation and functions of type III interferons in antiviral immunity.

  2015cites this paper
• Nanotherapy for Cancer: Targeting and Multifunctionality in the Future of Cancer Therapies

  2015cites this paper
• RNA interference approaches for treatment of HIV-1 infection

  2015cites this paper
• IFI16: At the interphase between innate DNA sensing and genome regulation.

  2014cites this paper
• Bacterial expression of the HINab domain of IFI16: purification, characterization of DNA binding activity, and co-crystallization with viral dsDNA.

  2014cites this paper
• HIV-1 Treated Patients with Undetectable Viral Loads have Lower Levels of Innate Immune Responses via Cytosolic DNA Sensing Systems Compared with Healthy Uninfected Controls

  2014cites this paper
• The Unique Regulation and Functions of Type Iii Interferons in Antiviral Immunity This Review Comes from a Themed Issue on Antiviral Strategies Ifnlr Signaling Type Iii Ifn Targets and Biological Activities Sciencedirect Regulation of Type Iii Ifn Expression

  year unknowncites this paper