scholarly journals Pseudorabies Virus dUTPase UL50 Induces Lysosomal Degradation of Type I Interferon Receptor 1 and Antagonizes the Alpha Interferon Response

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Rui Zhang ◽  
Aotian Xu ◽  
Chao Qin ◽  
Qiong Zhang ◽  
Shifan Chen ◽  
...  
Keyword(s):  
Pseudorabies Virus ◽  
Type I Interferon ◽  
Antiviral Drug ◽  
Ectopic Expression ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Lysosomal Degradation ◽  
Independent Manner ◽  
Strong Inhibitor

ABSTRACT Alphaherpesviruses that establish persistent infections rely partly on their ability to evade host antiviral responses, notably the type I interferon (IFN) response. However, the mechanisms employed by alphaherpesviruses to avoid this response are not well understood. Pseudorabies virus (PRV) is an economically important pathogen and a useful model system for studying alphaherpesvirus biology. To identify PRV proteins that antagonize type I IFN signaling, we performed a screen by using an IFN-stimulated response element reporter in the swine cell line CRL. Unexpectedly, we identified the dUTPase UL50 as a strong inhibitor. We confirmed that UL50 has the ability to inhibit type I IFN signaling by performing ectopic expression of UL50 in cells and deletion of UL50 in PRV. Mechanistically, UL50 impeded type I IFN-induced STAT1 phosphorylation, likely by accelerating lysosomal degradation of IFN receptor 1 (IFNAR1). In addition, this UL50 activity was independent of its dUTPase activity and required amino acids 225 to 253 in the C-terminal region. The UL50 encoded by herpes simplex virus 1 (HSV-1) also possessed similar activity. Moreover, UL50-deleted PRV was more susceptible to IFN than UL50-proficient PRV. Our results suggest that in addition to its dUTPase activity, the UL50 protein of alphaherpesviruses possesses the ability to suppress type I IFN signaling by promoting lysosomal degradation of IFNAR1, thereby contributing to immune evasion. This finding reveals UL50 as a potential antiviral target. IMPORTANCE Alphaherpesviruses can establish lifelong infections and cause many diseases in humans and animals. Pseudorabies virus (PRV) is a swine alphaherpesvirus that threatens pig production. Using PRV as a model, we found that this alphaherpesvirus could utilize its encoded dUTPase UL50 to induce IFNAR1 degradation and inhibit type I IFN signaling in an enzymatic activity-independent manner. Our finding reveals a mechanism employed by an alphaherpesvirus to evade the immune response and indicates that UL50 is an important viral protein in pathogenesis and is a potential target for antiviral drug development.

scholarly journals The role of the Type I interferon response in the resistance of mice to filovirus infection

2001 ◽  
Vol 82 (6) ◽  
pp. 1365-1373 ◽  
Author(s):  
Mike Bray
Keyword(s):  
Type I Interferon ◽  
Antiviral Drug ◽  
Interferon Response ◽  
Type I ◽  
Antibody Treatment ◽  
Adult Mice ◽  
Lethal Infection ◽  
Series Of Experiments ◽  
Β Receptor ◽  
Immunocompetent Mice

Adult immunocompetent mice inoculated with Ebola (EBO) or Marburg (MBG) virus do not become ill. A suckling-mouse-passaged variant of EBO Zaire ’76 (‘mouse-adapted EBO-Z’) causes rapidly lethal infection in adult mice after intraperitoneal (i.p.) inoculation, but does not cause apparent disease when inoculated subcutaneously (s.c.). A series of experiments showed that both forms of resistance to infection are mediated by the Type I interferon response. Mice lacking the cell-surface IFN-α/β receptor died within a week after inoculation of EBO-Z ’76, EBO Sudan, MBG Musoke or MBG Ravn, or after s.c. challenge with mouse-adapted EBO-Z. EBO Reston and EBO Ivory Coast did not cause illness, but immunized the mice against subsequent challenge with mouse-adapted EBO-Z. Normal adult mice treated with antibodies against murine IFN-α/β could also be lethally infected with i.p.-inoculated EBO-Z ’76 or EBO Sudan and with s.c.-inoculated mouse-adapted EBO-Z. Severe combined immunodeficient (SCID) mice became ill 3–4 weeks after inoculation with EBO-Z ’76, EBO Sudan or MBG Ravn, but not the other viruses. Treatment with anti-IFN-α/β antibodies markedly accelerated the course of EBO-Z ’76 infection. Antibody treatment blocked the effect of a potent antiviral drug, 3-deazaneplanocin A, indicating that successful filovirus therapy may require the active participation of the Type I IFN response. Mice lacking an IFN-α/β response resemble primates in their susceptibility to rapidly progressive, overwhelming filovirus infection. The outcome of filovirus transfer between animal species appears to be determined by interactions between the virus and the innate immune response.

scholarly journals The Interferon-Induced Exonuclease ISG20 Exerts Antiviral Activity through Upregulation of Type I Interferon Response Proteins

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Christopher M. Weiss ◽  
Derek W. Trobaugh ◽  
Chengqun Sun ◽  
Tiffany M. Lucas ◽  
Michael S. Diamond ◽  
...  
Keyword(s):  
Virus Replication ◽  
Type I Interferon ◽  
Rna Virus ◽  
Ectopic Expression ◽  
Viral Rna ◽  
Interferon Response ◽  
Type I ◽  
Venezuelan Equine Encephalitis ◽  
Wild Type ◽  
In Cells

ABSTRACTType I interferon (IFN)-stimulated genes (ISGs) have critical roles in inhibiting virus replication and dissemination. Despite advances in understanding the molecular basis of ISG restriction, the antiviral mechanisms of many remain unclear. The 20-kDa ISG ISG20 is a nuclear 3′–5′ exonuclease with preference for single-stranded RNA (ssRNA) and has been implicated in the IFN-mediated restriction of several RNA viruses. Although the exonuclease activity of ISG20 has been shown to degrade viral RNAin vitro, evidence has yet to be presented that virus inhibition in cells requires this activity. Here, we utilized a combination of an inducible, ectopic expression system and newly generatedIsg20−/−mice to investigate mechanisms and consequences of ISG20-mediated restriction. Ectopically expressed ISG20 localized primarily to Cajal bodies in the nucleus and restricted replication of chikungunya and Venezuelan equine encephalitis viruses. Although restriction by ISG20 was associated with inhibition of translation of infecting genomic RNA, degradation of viral RNAs was not observed. Instead, translation inhibition of viral RNA was associated with ISG20-induced upregulation of over 100 other genes, many of which encode known antiviral effectors. ISG20 modulated the production of IFIT1, an ISG that suppresses translation of alphavirus RNAs. Consistent with this observation, the pathogenicity of IFIT1-sensitive alphaviruses was increased inIsg20−/−mice compared to that of wild-type viruses but not in cells ectopically expressing ISG20. Our findings establish an indirect role for ISG20 in the early restriction of RNA virus replication by regulating expression of other ISGs that inhibit translation and possibly other activities in the replication cycle.IMPORTANCEThe host immune responses to infection lead to the production of type I interferon (IFN), and the upregulation of interferon-stimulated genes (ISGs) reduces virus replication and virus dissemination within a host. Ectopic expression of the interferon-induced 20-kDa exonuclease ISG20 suppressed replication of chikungunya virus and Venezuelan equine encephalitis virus, two mosquito-vectored RNA alphaviruses. Since the replication of alphavirus genomes occurs exclusively in the cytoplasm, the mechanism of nucleus-localized ISG20 inhibition of replication is unclear. In this study, we determined that ISG20 acts as a master regulator of over 100 genes, many of which are ISGs. Specifically, ISG20 upregulated IFIT1 genes and inhibited translation of the alphavirus genome. Furthermore, IFIT1-sensitive alphavirus replication was increased inIsg20−/−mice compared to the replication of wild-type viruses but not in cells ectopically expressing ISG20. We propose that ISG20 acts as an indirect regulator of RNA virus replication in the cytoplasm through the upregulation of many other ISGs.

scholarly journals Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant

2009 ◽  
Vol 206 (7) ◽  
pp. 1589-1602 ◽  
Author(s):  
M. Paula Longhi ◽  
Christine Trumpfheller ◽  
Juliana Idoyaga ◽  
Marina Caskey ◽  
Ines Matos ◽  
...  
Keyword(s):  
T Cell ◽  
Type I Interferon ◽  
Host Cells ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Protein Vaccine ◽  
Adaptive Responses ◽  
Cell Repertoire ◽  
Gag Protein

Relative to several other toll-like receptor (TLR) agonists, we found polyinosinic:polycytidylic acid (poly IC) to be the most effective adjuvant for Th1 CD4+ T cell responses to a dendritic cell (DC)–targeted HIV gag protein vaccine in mice. To identify mechanisms for adjuvant action in the intact animal and the polyclonal T cell repertoire, we found poly IC to be the most effective inducer of type I interferon (IFN), which was produced by DEC-205+ DCs, monocytes, and stromal cells. Antibody blocking or deletion of type I IFN receptor showed that IFN was essential for DC maturation and development of CD4+ immunity. The IFN-AR receptor was directly required for DCs to respond to poly IC. STAT 1 was also essential, in keeping with the type I IFN requirement, but not type II IFN or IL-12 p40. Induction of type I IFN was mda5 dependent, but DCs additionally used TLR3. In bone marrow chimeras, radioresistant and, likely, nonhematopoietic cells were the main source of IFN, but mda5 was required in both marrow–derived and radioresistant host cells for adaptive responses. Therefore, the adjuvant action of poly IC requires a widespread innate type I IFN response that directly links antigen presentation by DCs to adaptive immunity.

scholarly journals The NS2 Protein of Human Respiratory Syncytial Virus Suppresses the Cytotoxic T-Cell Response as a Consequence of Suppressing the Type I Interferon Response

2006 ◽  
Vol 80 (12) ◽  
pp. 5958-5967 ◽  
Author(s):  
Alexander Kotelkin ◽  
Igor M. Belyakov ◽  
Lijuan Yang ◽  
Jay A. Berzofsky ◽  
Peter L. Collins ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Type I Interferon ◽  
Human Respiratory Syncytial Virus ◽  
Interferon Response ◽  
Cytotoxic T Cell ◽  
Type I ◽  
Type I Ifn ◽  
Ifn Γ ◽  
Syncytial Virus

ABSTRACT The NS1 and NS2 proteins of human respiratory syncytial virus (HRSV) have been shown to antagonize the type I interferon (IFN) response, an effect subject to host range constraints. We have now found that the HRSV NS2 protein strongly controls IFN induction in mouse cells in vitro, validating the use of the mouse model to study the consequences of these gene deletions on host immunity. We evaluated the effects of deleting the NS1 and/or NS2 gene on the induction of HRSV-specific pulmonary cytotoxic T lymphocytes (CTL) in BALB/c and 129S6 mice in response to intranasal infection with HRSV lacking the NS1 and/or NS2 gene and subsequent challenge with wild-type (wt) HRSV. In mice infected with HRSV lacking the NS2 gene (ΔNS2) or lacking the NS2 gene in combination with the NS1 gene (ΔNS1/2 HRSV), the magnitude of the pulmonary CTL response was substantially elevated compared to that of mice infected with wt HRSV or the ΔNS1 mutant, whether measured by binding of CD8+ cells to an HRSV-specific major histocompatibility complex class I tetramer, by measurement of CD8+ cells secreting gamma interferon (IFN-γ) in response to specific in vitro stimulation, or by a standard chromium release cell-killing assay. In contrast, in STAT1 knockout mice, which lack responsiveness to type I IFN, the level of IFN-γ-secreting CD8+ cells was not significantly different for HRSV lacking the NS2 gene, suggesting that the increase in CTL observed in IFN-responsive mice is type I IFN dependent. Thus, the NS2 protein of HRSV suppresses the CTL component of the adaptive immune response, and this appears to be a consequence of its suppression of type I IFN.

scholarly journals Hypoxia induces transcriptional and translational downregulation of the type I interferon (IFN) pathway in multiple cancer cell types

2019 ◽  
Author(s):  
Ana Miar ◽  
Esther Arnaiz ◽  
Esther Bridges ◽  
Shaunna Beedie ◽  
Adam P Cribbs ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Type I Interferon ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Type I ◽  
Type I Ifn ◽  
Multiple Cancer ◽  
Independent Manner

AbstractHypoxia is a common phenomenon in solid tumours and is considered a hallmark of cancer. Increasing evidence shows that hypoxia promotes local immune suppression. Type I IFN is involved in supporting cytotoxic T lymphocytes by stimulating the maturation of dendritic cells (DCs) and enhancing their capacity to process and present antigens. However, there is little information about the relationship between hypoxia and the type I interferon (IFN) pathway, which comprises the sensing of double-stranded RNA and DNA (dsRNA/dsDNA), followed by IFNα/β secretion and transcription activation of IFN-stimulated genes (ISGs). The aims of this study were to determine both the effect and mechanisms of hypoxia on the I IFN pathway in breast cancer.There was a downregulation of the type I IFN pathway expression at mRNA and protein level in cancer cell lines under hypoxia in vitro and in vivo in xenografts. This pathway was suppressed at each level of signalling, from the dsRNA sensors (RIG-I, MDA5), the adaptor (MAVS), transcription factors (IRF3, IRF7, STAT1) and several ISGs (RIG-I, IRF7, STAT1, ADAR-p150). There was also lower IFN secretion under hypoxic conditions. HIF1 and HIF2 regulation of gene expression did not explain most of the effects. However, ATAC-Seq data revealed that in hypoxia peaks with STAT1 and IRF3 motifs had decreased accessibility.Thus hypoxia leads to an overall 50% downregulation of the type I IFN pathway due to repressed transcription and lower chromatin accessibility in a HIF1/2α-independent manner, which could contribute to immunosuppression in hypoxic tumours.

scholarly journals Mycobacterium tuberculosis MmsA (Rv0753c) Interacts with STING and Blunts the Type I Interferon Response

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Yifan Sun ◽  
Wei Zhang ◽  
Chunsheng Dong ◽  
Sidong Xiong
Keyword(s):  
Mass Spectrometry ◽  
Mycobacterium Tuberculosis ◽  
Proteomic Analysis ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Content Type ◽  
C Terminus ◽  
Autophagic Degradation

ABSTRACT Type I interferon (IFN) plays an important role in Mycobacterium tuberculosis persistence and disease pathogenesis. M. tuberculosis has evolved a number of mechanisms to evade host immune surveillance. However, it is unclear how the type I IFN response is tightly regulated by the M. tuberculosis determinants. Stimulator of interferon genes (STING) is an essential adaptor for type I IFN production triggered by M. tuberculosis genomic DNA or cyclic dinucleotides upon infection. To investigate how the type I IFN response is regulated by M. tuberculosis determinants, immunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis was performed to screen proteins interacting with STING in the context of M. tuberculosis infection. Among the many predicted candidates interacting with STING, the M. tuberculosis coding protein Rv0753c (MmsA) was identified. We confirmed that MmsA binds and colocalizes with STING, and the N-terminal regions of MmsA (amino acids [aa] 1 to 251) and STING (aa 1 TO 190) are responsible for MmsA-STING interaction. Type I IFN production was impaired with exogenous expression of MmsA in RAW264.7 cells. MmsA inhibited the STING-TBK1-IRF3 pathway, as evidenced by reduced STING levelS and subsequent IRF3 activation. Furthermore, MmsA facilitated p62-mediated STING autophagic degradation by binding p62 with its C terminus (aa 252 to 455), which may account for the negative regulation of M. tuberculosis MmsA in STING-mediated type I IFN production. Additionally, the M. tuberculosis mmsA R138W mutation, detected in a hypervirulent clinical isolate, enhanced the degradation of STING, implying the important relevance of MmsA in disease outcome. Together, we report a novel mechanism where M. tuberculosis MmsA serves as an antagonist of type I IFN response by targeting STING with p62-mediated autophagic degradation. IMPORTANCE It is unclear how the type I IFN response is regulated by mycobacterial determinants. Here, we characterized the previously unreported role of M. tuberculosis MmsA in immunological regulation of type I IFN response by targeting the central adaptor STING in the DNA sensing pathway. We identified STING-interacting MmsA by coimmunoprecipitation-mass spectrometry-based (IP-MS) proteomic analysis and showed MmsA interacting with STING and autophagy receptor p62 via its N terminus and C terminus, respectively. We also showed that MmsA downregulated type I IFN by promoting p62-mediated STING degradation. Moreover, the MmsA mutant R138W is potentially associated with the virulence of M. tuberculosis clinical strains owing to the modulation of STING protein. Our results provide novel insights into the regulatory mechanism of type I IFN response manipulated by mycobacterial MmsA and the additional cross talk between autophagy and STING in M. tuberculosis infection, wherein a protein from microbial pathogens induces autophagic degradation of host innate immune molecules.

scholarly journals Inhibition of the Type I Interferon Response in Human Dendritic Cells by Dengue Virus Infection Requires a Catalytically Active NS2B3 Complex

2010 ◽  
Vol 84 (19) ◽  
pp. 9760-9774 ◽  
Author(s):  
Juan R. Rodriguez-Madoz ◽  
Alan Belicha-Villanueva ◽  
Dabeiba Bernal-Rubio ◽  
Joseph Ashour ◽  
Juan Ayllon ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dengue Virus ◽  
Type I Interferon ◽  
Poly I:C ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Human Virus ◽  
Catalytically Active ◽  
Human Dendritic Cells

ABSTRACT Dengue virus (DENV) is the most prevalent arthropod-borne human virus, able to infect and replicate in human dendritic cells (DCs), inducing their activation and the production of proinflammatory cytokines. However, DENV can successfully evade the immune response in order to produce disease in humans. Several mechanisms of immune evasion have been suggested for DENV, most of them involving interference with type I interferon (IFN) signaling. We recently reported that DENV infection of human DCs does not induce type I IFN production by those infected DCs, impairing their ability to prime naive T cells toward Th1 immunity. In this article, we report that DENV also reduces the ability of DCs to produce type I IFN in response to several inducers, such as infection with other viruses or exposure to Toll-like receptor (TLR) ligands, indicating that DENV antagonizes the type I IFN production pathway in human DCs. DENV-infected human DCs showed a reduced type I IFN response to Newcastle disease virus (NDV), Sendai virus (SeV), and Semliki Forest virus (SFV) infection and to the TLR3 agonist poly(I:C). This inhibitory effect is DENV dose dependent, requires DENV replication, and takes place in DENV-infected DCs as early as 2 h after infection. Expressing individual proteins of DENV in the presence of an IFN-α/β production inducer reveals that a catalytically active viral protease complex is required to reduce type I IFN production significantly. These results provide a new mechanism by which DENV evades the immune system in humans.

scholarly journals Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3

2018 ◽  
Author(s):  
Chao Qin ◽  
Rui Zhang ◽  
Yue Lang ◽  
Anwen Shao ◽  
Aotian Xu ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Pseudorabies Virus ◽  
Viral Infections ◽  
Type I Interferon ◽  
Interferon Response ◽  
Interferon Α ◽  
Type I ◽  
Viral Inhibition ◽  
Simplex Virus ◽  
Hsv 1

AbstractType I interferon response plays a prominent role against viral infection, which is frequently disrupted by viruses. Here, we report Bcl-2 associated transcription factor 1 (Bclaf1) is degraded during the alphaherpesvirus Pseudorabies virus (PRV) and Herpes simplex virus type 1 (HSV-1) infections through the viral protein US3. We further reveal that Bclaf1 functions critically in type I interferon signaling. Knockdown or knockout of Bclaf1 in cells significantly impairs interferon-α (IFNα)-mediated gene transcription and viral inhibition against US3 deficient PRV and HSV-1. Mechanistically, Bclaf1 maintains a mechanism allowing STAT1 and STAT2 to be efficiently phosphorylated in response to IFNα, and more importantly, facilitates IFN-stimulated gene factor 3 (ISGF3) binding with IFN-stimulated response elements (ISRE) for efficient gene transcription by directly interacting with ISRE and STAT2. Our studies establish the importance of Bclaf1 in IFNα-induced antiviral immunity and in the control of viral infections.

scholarly journals Cyclic di-AMP Released from Staphylococcus aureus Biofilm Induces a Macrophage Type I Interferon Response

2016 ◽  
Vol 84 (12) ◽  
pp. 3564-3574 ◽  
Author(s):  
Casey M. Gries ◽  
Eric L. Bruger ◽  
Derek E. Moormeier ◽  
Tyler D. Scherr ◽  
Christopher M. Waters ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Bacterial Infections ◽  
Type I Interferon ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn ◽  
Biofilm Growth ◽  
Content Type ◽  
Anti Inflammatory

Staphylococcus aureus is a leading cause of community- and nosocomial-acquired infections, with a propensity for biofilm formation. S. aureus biofilms actively skew the host immune response toward an anti-inflammatory state; however, the biofilm effector molecules and the mechanism(s) of action responsible for this phenomenon remain to be fully defined. The essential bacterial second messenger cyclic diadenylate monophosphate (c-di-AMP) is an emerging pathogen-associated molecular pattern during intracellular bacterial infections, as c-di-AMP secretion into the infected host cytosol induces a robust type I interferon (IFN) response. Type I IFNs have the potential to exacerbate infectious outcomes by promoting anti-inflammatory effects; however, the type I IFN response to S. aureus biofilms is unknown. Additionally, while several intracellular proteins function as c-di-AMP receptors in S. aureus , it has yet to be determined if any extracellular role for c-di-AMP exists and its release during biofilm formation has not yet been demonstrated. This study examined the possibility that c-di-AMP released during S. aureus biofilm growth polarizes macrophages toward an anti-inflammatory phenotype via type I interferon signaling. DacA, the enzyme responsible for c-di-AMP synthesis in S. aureus , was highly expressed during biofilm growth, and 30 to 50% of total c-di-AMP produced from S. aureus biofilm was released extracellularly due to autolytic activity. S. aureus biofilm c-di-AMP release induced macrophage type I IFN expression via a STING-dependent pathway and promoted S. aureus intracellular survival in macrophages. These findings identify c-di-AMP as another mechanism for how S. aureus biofilms promote macrophage anti-inflammatory activity, which likely contributes to biofilm persistence.

scholarly journals TRIM14 is a key regulator of the type I interferon response during Mycobacterium tuberculosis infection

2019 ◽  
Author(s):  
Caitlyn T. Hoffpauir ◽  
Samantha L. Bell ◽  
Kelsi O. West ◽  
Tao Jing ◽  
Sylvia Torres-Odio ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Nucleic Acid ◽  
Type I Interferon ◽  
Negative Regulator ◽  
Interferon Response ◽  
Cytokine Signaling ◽  
Type I ◽  
Type I Ifn ◽  
Mycobacterium Tuberculosis Infection ◽  
Innate Immune Signaling

ABSTRACTTripartite motif-containing proteins (TRIMs) play a variety of recently described roles in innate immunity. While many TRIMs regulate type I interferon (IFN) expression following cytosolic nucleic acid sensing of viruses, their contribution to innate immune signaling and gene expression during bacterial infection remains largely unknown. Because Mycobacterium tuberculosis is a potent activator of cGAS-dependent cytosolic DNA sensing, we set out to investigate a role for TRIM proteins in regulating macrophage responses to M. tuberculosis. Here we demonstrate that TRIM14, a non-canonical TRIM that lacks an E3 ligase RING domain, is a critical negative regulator of the type I IFN response in macrophages. We show that TRIM14 physically interacts with both cGAS and TBK1 and that macrophages lacking TRIM14 dramatically hyperinduce interferon stimulated gene (ISG) expression following cytosolic nucleic acid transfection, IFN-β treatment, and M. tuberculosis infection. Consistent with a defect in resolution of the type I IFN response, Trim14 knockout (KO) macrophages have more phospho-Ser754 STAT3 relative to phospho-727 and fail to upregulate the STAT3 target Socs3 (Suppressor of Cytokine Signaling 3), which is required to turn off IFNAR signaling. These data support a model whereby TRIM14 acts as a scaffold between TBK1 and STAT3 to promote phosphorylation of STAT3 at Ser727 and enhance negative regulation of ISG expression. Remarkably, Trim14 KO macrophages hyperinduce antimicrobials like Inos2 and are significantly better than control cells at limiting M. tuberculosis replication. Collectively, these data reveal a previously unappreciated role for TRIM14 in resolving type I IFN responses and controlling M. tuberculosis infection.

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