Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

JMJD6 negatively regulates cytosolic RNA induced antiviral signaling by recruiting RNF5 to promote activated IRF3 K48 ubiquitination.

ABSTRACT: The negative regulation of antiviral immune responses is essential for the host to maintain homeostasis. Jumonji domain-containing protein 6 (JMJD6) was previously identified with a number of functions during RNA virus infection. Upon viral RNA recognition, retinoic acid-inducible gene-I-like receptors (RLRs) physically interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type-I interferon (IFN-I) production. Here, JMJD6 was demonstrated to reduce type-I interferon (IFN-I) production in response to cytosolic poly (I:C) and RNA virus infections, including Sendai virus (SeV) and Vesicular stomatitis virus (VSV). Genetic inactivation of JMJD6 enhanced IFN-I production and impaired viral replication. Our unbiased proteomic screen demonstrated JMJD6 contributes to IRF3 K48 ubiquitination degradation in an RNF5-dependent manner. Mice with gene deletion of JMJD6 through piggyBac transposon-mediated gene transfer showed increased VSV-triggered IFN-I production and reduced susceptibility to the virus. These findings classify JMJD6 as a negative regulator of the host's innate immune responses to cytosolic viral RNA.

SUBMITTER: Zhang W

PROVIDER: S-EPMC7971890 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

TRAF3IP3 negatively regulates cytosolic RNA induced anti-viral signaling by promoting TBK1 K48 ubiquitination.

Project description:Innate immunity to nucleic acids forms the backbone for anti-viral immunity and several inflammatory diseases. Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type I interferon (IFN-I). TRAF3-interacting protein 3 (TRAF3IP3, T3JAM) is essential for T and B cell development. It is also well-expressed by myeloid cells, where its role is unknown. Here we report that TRAF3IP3 suppresses cytosolic poly(I:C), 5'ppp-dsRNA, and vesicular stomatitis virus (VSV) triggers IFN-I expression in overexpression systems and Traf3ip3-/- primary myeloid cells. The mechanism of action is through the interaction of TRAF3IP3 with endogenous TRAF3 and TBK1. This leads to the degradative K48 ubiquitination of TBK1 via its K372 residue in a DTX4-dependent fashion. Mice with myeloid-specific gene deletion of Traf3ip3 have increased RNA virus-triggered IFN-I production and reduced susceptibility to virus. These results identify a function of TRAF3IP3 in the regulation of the host response to cytosolic viral RNA in myeloid cells.

| S-EPMC7198545 | biostudies-literature

Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation.

Project description:Cytosolic RNA/DNA sensing elicits primary defense against viral pathogens. Interferon regulatory factor 3 (IRF3), a key signal mediator/transcriptional factor of the antiviral-sensing pathway, is indispensible for interferon production and antiviral defense. However, how the status of IRF3 activation is controlled remains elusive. Through a functional screen of the human kinome, we found that mammalian sterile 20-like kinase 1 (Mst1), but not Mst2, profoundly inhibited cytosolic nucleic acid sensing. Mst1 associated with IRF3 and directly phosphorylated IRF3 at Thr75 and Thr253. This Mst1-mediated phosphorylation abolished activated IRF3 homodimerization, its occupancy on chromatin, and subsequent IRF3-mediated transcriptional responses. In addition, Mst1 also impeded virus-induced activation of TANK-binding kinase 1 (TBK1), further attenuating IRF3 activation. As a result, Mst1 depletion or ablation enabled an enhanced antiviral response and defense in cells and mice. Therefore, the identification of Mst1 as a novel physiological negative regulator of IRF3 activation provides mechanistic insights into innate antiviral defense and potential antiviral prevention strategies.

| S-EPMC4863739 | biostudies-literature

HSCARG negatively regulates the cellular antiviral RIG-I like receptor signaling pathway by inhibiting TRAF3 ubiquitination via recruiting OTUB1.

Project description:RIG-I like receptors (RLRs) recognize cytosolic viral RNA and initiate innate immunity; they increase the production of type I interferon (IFN) and the transcription of a series of antiviral genes to protect the host organism. Accurate regulation of the RLR pathway is important for avoiding tissue injury induced by excessive immune response. HSCARG is a newly reported negative regulator of NF-κB. Here we demonstrated that HSCARG participates in innate immunity. HSCARG inhibited the cellular antiviral response in an NF-κB independent manner, whereas deficiency of HSCARG had an opposite effect. After viral infection, HSCARG interacted with tumor necrosis receptor-associated factor 3 (TRAF3) and inhibited its ubiquitination by promoting the recruitment of OTUB1 to TRAF3. Knockout of HSCARG attenuated the de-ubiquitination of TRAF3 by OTUB1, and knockdown of OTUB1 abolished the effect of HSCARG. HSCARG also interacted with Ikappa-B kinase epsilon (IKKε) after viral infection and impaired the association between TRAF3 and IKKε, which further decreased the phosphorylation of IKKε and interferon response factor 3 (IRF3), thus suppressed the dimerization and nuclear translocation of IRF3. Moreover, knockdown of TRAF3 dampened the inhibitory effect of IFN-β transcription by HSCARG, suggesting that TRAF3 is necessary for HSCARG to down-regulate RLR pathway. This study demonstrated that HSCARG is a negative regulator that enables balanced antiviral innate immunity.

| S-EPMC3999155 | biostudies-literature

E3 ligase RNF99 negatively regulates TLR-mediated inflammatory immune response via K48-linked ubiquitination of TAB2.

Project description:Innate immunity is the first line to defend against pathogenic microorganisms, and Toll-like receptor (TLR)-mediated inflammatory responses are an essential component of innate immunity. However, the regulatory mechanisms of TLRs in innate immunity remain unperfected. We found that the expression of E3 ligase Ring finger protein 99 (RNF99) decreased significantly in peripheral blood monocytes from patients infected with Gram negative bacteria (G-) and macrophages stimulated by TLRs ligands, indicating the role of RNF99. We also demonstrated for the first time, the protective role of RNF99 against LPS-induced septic shock and dextran sodium sulfate (DSS)-induced colitis using RNF99 knockout mice (RNF99-/-) and bone marrow-transplanted mice. In vitro experiments revealed that RNF99 deficiency significantly promoted TLR-mediated inflammatory cytokine expression and activated the NF-κB and MAPK pathways in macrophages. Mechanistically, in both macrophages and HEK293 cell line with TLR4 stably transfection, RNF99 interacted with and degraded TAK1-binding protein (TAB) 2, a regulatory protein of the kinase TAK1, via the lysine (K)48-linked ubiquitin-proteasomal pathway on lysine 611 of TAB2, which further regulated the TLR-mediated inflammatory response. Overall, these findings indicated the physiological significance of RNF99 in macrophages in regulating TLR-mediated inflammatory reactions. It provided new insight into TLRs signal transduction, and offered a novel approach for preventing bacterial infections, endotoxin shock, and other inflammatory ills.

| S-EPMC10070438 | biostudies-literature

TOB1 attenuates IRF3-directed antiviral responses by recruiting HDAC8 to specifically suppress IFN-β expression.

Project description:Interferon regulatory factor 3 (IRF3) is a key transcription factor required for the secretion of type I interferons (IFN-α/β) and initiation of antiviral immune response. However, the negative feedback regulator of IRF3-directed antiviral response remains unknown. In this study, we demonstrated that viral infection induced the interaction of the transducer of ERBB2.1 (TOB1) with IRF3, which bound to the promoter region of Ifnb1 in macrophages. TOB1 inhibited Ifnb1 transcription by disrupting IRF3 binding and recruiting histone deacetylase 8 (HDAC8) to the Ifnb1 promoter region. Consequently, TOB1 attenuated IRF3-directed IFN-β expression in virus-infected macrophages. Tob1 deficiency enhanced antiviral response and suppressed viral replication in vivo. Thus, we identified TOB1 as a feedback inhibitor of host antiviral innate immune response and revealed a mechanism underlying viral immune escape.

| S-EPMC9463440 | biostudies-literature

TRIM26 negatively regulates interferon-β production and antiviral response through polyubiquitination and degradation of nuclear IRF3.

Project description:Virus infection leads to the activation of transcription factor IRF3 and subsequent production of type I inteferons, which induce the transcription of various antiviral genes called interferon stimulated genes (ISGs) to eliminate viral infection. IRF3 activation requires phosphorylation, dimerization and nuclear translocation. However, the mechanisms for the termination of IRF3 activation in nucleus are elusive. Here we report the identification of TRIM26 to negatively regulate IFN-β production and antiviral response by targeting nuclear IRF3. TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus. TRIM26 degraded WT IRF3 and the constitutive active mutant IRF3 5D, but not the phosphorylation deficient mutant IRF3 5A. Furthermore, IRF3 mutant in the Nuclear Localization Signal (NLS), which could not move into nucleus, was not degraded by TRIM26. Importantly, virus infection promoted TRIM26 nuclear translocation, which was required for IRF3 degradation. As a consequence, TRIM26 attenuated IFN-β promoter activation and IFN-β production downstream of TLR3/4, RLR and DNA sensing pathways. TRIM26 transgenic mice showed much less IRF3 activation and IFN-β production, while increased virus replication. Our findings delineate a novel mechanism for the termination of IRF3 activation in nucleus through TRIM26-mediated IRF3 ubiquitination and degradation.

| S-EPMC4357427 | biostudies-literature

USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA.

Project description:Mediator of IRF3 activation (MITA, also known as STING and ERIS) is an essential adaptor protein for cytoplasmic DNA-triggered signaling and involved in innate immune responses, autoimmunity and tumorigenesis. The activity of MITA is critically regulated by ubiquitination and deubiquitination. Here, we report that USP49 interacts with and deubiquitinates MITA after HSV-1 infection, thereby turning down cellular antiviral responses. Knockdown or knockout of USP49 potentiated HSV-1-, cytoplasmic DNA- or cGAMP-induced production of type I interferons (IFNs) and proinflammatory cytokines and impairs HSV-1 replication. Consistently, Usp49-/- mice exhibit resistance to lethal HSV-1 infection and attenuated HSV-1 replication compared to Usp49+/+ mice. Mechanistically, USP49 removes K63-linked ubiquitin chains from MITA after HSV-1 infection which inhibits the aggregation of MITA and the subsequent recruitment of TBK1 to the signaling complex. These findings suggest a critical role of USP49 in terminating innate antiviral responses and provide insights into the complex regulatory mechanisms of MITA activation.

| S-EPMC6464240 | biostudies-literature

The ubiquitin E3 ligase RAUL negatively regulates type i interferon through ubiquitination of the transcription factors IRF7 and IRF3.

Project description:In the course of combating infectious agents, type I interferon (IFN) needs a timely downregulation mechanism to avoid detrimental overreaction. Here we showed a mechanism for restraining type I IFN responses, which relied on a HECT domain ubiquitin (Ub) E3 ligase, RAUL. RAUL limited type I IFN production by directly catalyzing lysine 48-linked polyubiquitination of both interferon regulatory factor 7 (IRF7) and IRF3 followed by proteasome-dependent degradation. Suppression of RAUL by dominant-negative RAUL or siRNA augmented both basal and virus-induced production of type I IFN, which resulted in reduced viral replication. The Kaposi's sarcoma-associated herpes virus immediate-early lytic cycle trigger protein RTA recruited this mechanism to augment its countermeasures against the host antiviral response. These results unveil a previously unrecognized "brake mechanism" for type I IFN that maintains proper low amounts of type I IFN under physiological conditions and restrains its magnitude when the antiviral response intensifies.

| S-EPMC3012379 | biostudies-literature

Ubiquitination of STING at lysine 224 controls IRF3 activation.

Project description:Cytosolic DNA species derived from invading microbes or leaked from the nuclear or mitochondrial compartments of the cell can trigger the induction of host defense genes by activating the endoplasmic reticulum-associated protein STING (stimulator of interferon genes). Using a mass spectrometry-based approach, we show that after association with cyclic dinucleotides, delivery of Tank-binding kinase 1 to interferon regulatory factors (IRFs), such as IRF3, relies on K63-linked ubiquitination of K224 on STING. Blocking K224 ubiquitination specifically prevented IRF3 but not nuclear factor ?B activation, additionally indicating that STING trafficking is not required to stimulate the latter signaling pathway. By carrying out a limited small interfering RNA screen, we have identified MUL1 (mitochondrial E3 ubiquitin protein ligase 1) as an E3 ligase that catalyzes the ubiquitination of STING on K224. These data demonstrate the critical role of K224 ubiquitination in STING function and provide molecular insight into the mechanisms governing host defense responses.

| S-EPMC5656267 | biostudies-literature

Germ-Cell-Specific Inflammasome Component NLRP14 Negatively Regulates Cytosolic Nucleic Acid Sensing to Promote Fertilization.

Project description:Cytosolic sensing of nucleic acids initiates tightly regulated programs to limit infection. Oocyte fertilization represents a scenario wherein inappropriate responses to exogenous yet non-pathogen-derived nucleic acids would have negative consequences. We hypothesized that germ cells express negative regulators of nucleic acid sensing (NAS) in steady state and applied an integrated data-mining and functional genomics approach to identify a rheostat of DNA and RNA sensing-the inflammasome component NLRP14. We demonstrated that NLRP14 interacted physically with the nucleic acid sensing pathway and targeted TBK1 (TANK binding kinase 1) for ubiquitination and degradation. We further mapped domains in NLRP14 and TBK1 that mediated the inhibitory function. Finally, we identified a human nonsense germline variant associated with male sterility that results in loss of NLRP14 function and hyper-responsiveness to nucleic acids. The discovery points to a mechanism of nucleic acid sensing regulation that may be of particular importance in fertilization.

| S-EPMC5674777 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data