RESUMEN
Oxygen is essential for aerobic organisms, but little is known about its role in antiviral immunity. Here, we report that during responses to viral infection, hypoxic conditions repress antiviral-responsive genes independently of HIF signaling. EGLN1 is identified as a key mediator of the oxygen enhancement of antiviral innate immune responses. Under sufficient oxygen conditions, EGLN1 retains its prolyl hydroxylase activity to catalyze the hydroxylation of IRF3 at proline 10. This modification enhances IRF3 phosphorylation, dimerization and nuclear translocation, leading to subsequent IRF3 activation. Furthermore, mice and zebrafish with Egln1 deletion, treatment with the EGLN inhibitor FG4592, or mice carrying an Irf3 P10A mutation are more susceptible to viral infections. These findings not only reveal a direct link between oxygen and antiviral responses, but also provide insight into the mechanisms by which oxygen regulates innate immunity.
Asunto(s)
Prolina Dioxigenasas del Factor Inducible por Hipoxia , Inmunidad Innata , Factor 3 Regulador del Interferón , Oxígeno , Prolina , Pez Cebra , Animales , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Factor 3 Regulador del Interferón/metabolismo , Hidroxilación , Humanos , Prolina/metabolismo , Ratones , Oxígeno/metabolismo , Células HEK293 , Fosforilación , Ratones Noqueados , Transducción de Señal , Ratones Endogámicos C57BLRESUMEN
To effectively protect the host from viral infection while avoiding excessive immunopathology, the innate immune response must be tightly controlled. However, the precise regulation of antiviral innate immunity and the underlying mechanisms remain unclear. Here, we find that sirtuin3 (SIRT3) interacts with mitochondrial antiviral signaling protein (MAVS) to catalyze MAVS deacetylation at lysine residue 7 (K7), which promotes MAVS aggregation, as well as TANK-binding kinase I and IRF3 phosphorylation, resulting in increased MAVS activation and enhanced type I interferon signaling. Consistent with these findings, loss of Sirt3 in mice and zebrafish renders them more susceptible to viral infection compared to their wild-type (WT) siblings. However, Sirt3 and Sirt5 double-deficient mice exhibit the same viral susceptibility as their WT littermates, suggesting that loss of Sirt5 in Sirt3-deficient mice may counteract the increased viral susceptibility displayed in Sirt3-deficient mice. Thus, we not only demonstrate that SIRT3 positively regulates antiviral immunity in vitro and in vivo, likely via MAVS, but also uncover a previously unrecognized mechanism by which SIRT3 acts as an accelerator and SIRT5 as a brake to orchestrate antiviral innate immunity.
Asunto(s)
Sirtuina 3 , Sirtuinas , Virosis , Animales , Ratones , Proteínas Adaptadoras Transductoras de Señales/genética , Inmunidad Innata , Lisina , Sirtuina 3/genética , Sirtuinas/genética , Pez Cebra , Proteínas de Pez CebraRESUMEN
HIF1α is one of the master regulators of the hypoxia signaling pathway and its activation is regulated by multiple post-translational modifications (PTMs). Deubiquitination mediated by deubiquitylating enzymes (DUBs) is an essential PTM that mainly modulates the stability of target proteins. USP38 belongs to the ubiquitin-specific proteases (USPs). However, whether USP38 can affect hypoxia signaling is still unknown. In this study, we used quantitative real-time PCR assays to identify USPs that can influence hypoxia-responsive gene expression. We found that overexpression of USP38 increased hypoxia-responsive gene expression, but knockout of USP38 suppressed hypoxia-responsive gene expression under hypoxia. Mechanistically, USP38 interacts with HIF1α to deubiquitinate K11-linked polyubiquitination of HIF1α at Lys769, resulting in stabilization and subsequent activation of HIF1α. In addition, we show that USP38 attenuates cellular ROS and suppresses cell apoptosis under hypoxia. Thus, we reveal a novel role for USP38 in the regulation of hypoxia signaling.
Asunto(s)
Hipoxia , Transducción de Señal , Humanos , Hipoxia de la Célula/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo , Ubiquitinación , Línea CelularRESUMEN
Activation of type I interferon (IFN-1) signaling is essential to protect host cells from viral infection. The full spectrum of IFN-I induction requires the activation of a number of cellular factors, including IκB kinase epsilon (IKKϵ). However, the regulation of IKKϵ activation in response to viral infection remains largely unknown. Here, we show that factor inhibiting hypoxia-inducible factor (HIF) (FIH), an asparaginyl hydroxylase, interacts with IKKϵ and catalyzes asparagine hydroxylation of IKKϵ at Asn-254, Asn-700, and Asn-701, resulting in the suppression of IKKϵ activation. FIH-mediated hydroxylation of IKKϵ prevents IKKϵ binding to TBK1 and TRAF3 and attenuates the cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex-catalyzed K63-linked polyubiquitination of IKKϵ at Lys-416. In addition, Fih-deficient mice and zebrafish are more resistant to viral infection. This work uncovers a previously unrecognized role of FIH in suppressing IKKϵ activation for IFN signaling and antiviral immune responses.
Asunto(s)
Quinasa I-kappa B , Virosis , Animales , Ratones , Quinasa I-kappa B/metabolismo , Proteínas Represoras/metabolismo , Secuencia de Aminoácidos , Hidroxilación , Pez Cebra/metabolismo , Inmunidad InnataRESUMEN
The cytosolic RNA and DNA sensors initiate type I interferon signaling when binding to RNA or DNA. To effectively protect the host against virus infection and concomitantly avoid excessive interferonopathy at resting states, these sensors must be tightly regulated. However, the key molecular mechanisms regulating these sensors' activation remain elusive. Here, we identify PRMT3, a type I protein arginine methyltransferase, as a negative regulator of cytosolic RNA and DNA sensors. PRMT3 interacts with RIG-I, MDA5, and cGAS and catalyzes asymmetric dimethylation of R730 on RIG-I, R822 on MDA5, and R111 on cGAS. These modifications reduce RNA-binding ability of RIG-I and MDA5 as well as DNA-binding ability and oligomerization of cGAS, leading to the inhibition of downstream type I interferon production. Furthermore, mice with loss of one copy of Prmt3 or in vivo treatment of the PRMT3 inhibitor, SGC707, are more resistant to RNA and DNA virus infection. Our findings reveal an essential role of PRMT3 in the regulation of antiviral innate immunity and give insights into the molecular regulation of cytosolic RNA and DNA sensors' activation.
Asunto(s)
Arginina , Interferón Tipo I , Animales , Ratones , ARN/genética , Antivirales/farmacología , Inmunidad Innata , ADN/genética , Nucleotidiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/genéticaRESUMEN
In mammals, the signaling adaptor mitochondrial antiviral signaling protein (MAVS) is a critical determinant in antiviral innate immunity. However, because of the lack of in vivo data, the physiological function of zebrafish mavs in response to viral infection is still not determined. In this study, we demonstrate that the long splicing isoform of zebrafish mavs promotes IFN regulatory factor 3 signaling and NF-κB signaling. Overexpression of this isoform of mavs enhances cellular antiviral responses. Disruption of mavs in zebrafish attenuates survival ratio on challenge with spring viremia of carp virus. Consistently, the antiviral-responsive genes and inflammatory genes are significantly reduced, and the replication of spring viremia of carp virus is increased in mavs-null zebrafish. Therefore, we provide in vivo evidence to support that zebrafish mavs is essential for antiviral innate immunity, similar to mammalian MAVS.
Asunto(s)
Antivirales , Pez Cebra , Animales , Pez Cebra/metabolismo , Antivirales/metabolismo , Viremia , Inmunidad Innata , Isoformas de Proteínas/metabolismo , Mamíferos/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismoRESUMEN
The signaling adaptor MAVS is a critical determinant in retinoic acid-inducible gene 1-like receptor signaling, and its activation is tightly controlled by multiple mechanisms in response to viral infection, including phosphorylation and ubiquitination. In this article, we demonstrate that zebrafish sirt5, one of the sirtuin family proteins, negatively regulates mavs-mediated antiviral innate immunity. Sirt5 is induced by spring viremia of carp virus (SVCV) infection and binds to mavs, resulting in attenuating phosphorylation and ubiquitination of mavs. Disruption of sirt5 in zebrafish promotes survival ratio after challenge with SVCV. Consistently, the antiviral responsive genes are enhanced, and the replication of SVCV is diminished in sirt5-dificient zebrafish. Therefore, we reveal a function of zebrafish sirt5 in the negative regulation of antiviral innate immunity by targeting mavs.
Asunto(s)
Sirtuinas , Pez Cebra , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Antivirales , Inmunidad Innata , Fosforilación , Rhabdoviridae , Sirtuinas/metabolismo , Tretinoina/metabolismo , Ubiquitinación , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Retinoic acid-inducible-I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and cyclic GMP-AMP synthase (cGAS) genes encode essential cytosolic receptors mediating antiviral immunity against viruses. Here, we show that OTUD3 has opposing role in response to RNA and DNA virus infection by removing distinct types of RIG-I/MDA5 and cGAS polyubiquitination. OTUD3 binds to RIG-I and MDA5 and removes K63-linked ubiquitination. This serves to reduce the binding of RIG-I and MDA5 to viral RNA and the downstream adaptor MAVS, leading to the suppression of the RNA virus-triggered innate antiviral responses. Meanwhile, OTUD3 associates with cGAS and targets at Lys279 to deubiquitinate K48-linked ubiquitination, resulting in the enhancement of cGAS protein stability and DNA-binding ability. As a result, Otud3-deficient mice and zebrafish are more resistant to RNA virus infection but are more susceptible to DNA virus infection. These findings demonstrate that OTUD3 limits RNA virus-triggered innate immunity but promotes DNA virus-triggered innate immunity.
Asunto(s)
Infecciones por Virus ADN , Inmunidad Innata , Infecciones por Virus ARN , Proteasas Ubiquitina-Específicas , Animales , Proteína 58 DEAD Box/metabolismo , Infecciones por Virus ADN/inmunología , Virus ADN , Enzimas Desubicuitinizantes , Helicasa Inducida por Interferón IFIH1/metabolismo , Ratones , Nucleotidiltransferasas , Infecciones por Virus ARN/inmunología , Virus ARN , ARN Viral/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo , Pez Cebra/metabolismoRESUMEN
As a main regulator of cellular responses to hypoxia, the protein stability of hypoxia-inducible factor (HIF)-1α is strictly controlled by oxygen tension dependent of PHDs-catalyzed protein hydroxylation and pVHL complex-mediated proteasomal degradation. Whether HIF-1α protein stability as well as its activity can be further regulated under hypoxia is not well understood. In this study, we found that OTUB1 augments hypoxia signaling independent of PHDs/VHL and FIH. OTUB1 binds to HIF-1α and depletion of OTUB1 reduces endogenous HIF-1α protein under hypoxia. In addition, OTUB1 inhibits K48-linked polyubiquitination of HIF-1α via its non-canonical inhibition of ubiquitination activity. Furthermore, OTUB1 promotes hypoxia-induced glycolytic reprogramming for cellular metabolic adaptation. These findings define a novel regulation of HIF-1α under hypoxia and demonstrate that OTUB1-mediated HIF-1α stabilization positively regulates HIF-1α transcriptional activity and benefits cellular hypoxia adaptation.
Asunto(s)
Hipoxia de la Célula , Enzimas Desubicuitinizantes , Subunidad alfa del Factor 1 Inducible por Hipoxia , Transducción de Señal , Hipoxia de la Célula/fisiología , Enzimas Desubicuitinizantes/genética , Enzimas Desubicuitinizantes/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , UbiquitinaciónRESUMEN
Designing and building artificial nanodevices and nanoarchitectures in living systems are extremely intriguing subjects in nanotechnology and synthetic biology. Taking advantage of cellular machinery and endogenous biomacromolecules, such as proteins, is key to achieving the precise and sophisticated manipulation of nanoarchitectures. In this study, we proposed a protein-mediated DNA self-assembly strategy in a molecular crowding environment. By carefully controlling the surface charge of basic nuclear proteins in a crowding environment that mimicked the intracellular environment, we demonstrated that highly positively charged protamine can assemble individual DNA strands into defined structures similar to a catalytic process manner. Successful self-assembly required an optimized protamine surface charge and a crowding environment; otherwise, this self-assembly was impossible. Polyacrylamide gel electrophoresis (PAGE), atomic force microscopy (AFM), and dynamic light scattering (DLS) results showed that tile-based DNA tubular structures, tetrahedra, and two dimensional DNA origami structures were successfully assembled. We inferred that the assembly process occurred between the arginine-rich domain of protamine and DNA strands that repeatedly interacted with each other in the viscous system. The current study provides a potential strategy to construct nanodevices in living systems and presents an alternative protein-DNA interaction for the potential fabrication of protein-DNA hybrid nanomaterials.
Asunto(s)
Nanoestructuras , Nanotecnología , ADN/química , Humanos , Microscopía de Fuerza Atómica , Nanoestructuras/química , Nanotecnología/métodos , Conformación de Ácido Nucleico , ProtaminasRESUMEN
Sirt7 is one member of the sirtuin family proteins with NAD (NAD+)-dependent histone deacetylase activity. In this study, we report that zebrafish sirt7 is induced upon viral infection, and overexpression of sirt7 suppresses cellular antiviral responses. Disruption of sirt7 in zebrafish increases the survival rate upon spring viremia of carp virus infection. Further assays indicate that sirt7 interacts with irf3 and irf7 and attenuates phosphorylation of irf3 and irf7 by preventing tbk1 binding to irf3 and irf7. In addition, the enzymatic activity of sirt7 is not required for sirt7 to repress IFN-1 activation. To our knowledge, this study provides novel insights into sirt7 function and sheds new light on the regulation of irf3 and irf7 by attenuating phosphorylation.
Asunto(s)
Carpas , Pez Cebra , Animales , Antivirales , Carpas/metabolismo , Factor 3 Regulador del Interferón/metabolismo , Factores Reguladores del Interferón/metabolismo , NAD/metabolismo , Fosforilación , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismoRESUMEN
TNFR-associated factor 6 (TRAF6) not only recruits TBK1/IKKε to MAVS upon virus infection but also catalyzes K63-linked polyubiquitination on substrate or itself, which is critical for NEMO-dependent and -independent TBK1/IKKε activation, leading to the production of type I IFNs. The regulation at the TRAF6 level could affect the activation of antiviral innate immunity. In this study, we demonstrate that zebrafish prmt2, a type I arginine methyltransferase, attenuates traf6-mediated antiviral response. Prmt2 binds to the C terminus of traf6 to catalyze arginine asymmetric dimethylation of traf6 at arginine 100, preventing its K63-linked autoubiquitination, which results in the suppression of traf6 activation. In addition, it seems that the N terminus of prmt2 competes with mavs for traf6 binding and prevents the recruitment of tbk1/ikkε to mavs. By zebrafish model, we show that loss of prmt2 promotes the survival ratio of zebrafish larvae after challenge with spring viremia of carp virus. Therefore, we reveal, to our knowledge, a novel function of prmt2 in the negative regulation of antiviral innate immunity by targeting traf6.
Asunto(s)
Inmunidad Innata/inmunología , Proteína-Arginina N-Metiltransferasas/inmunología , Infecciones por Rhabdoviridae/inmunología , Factor 6 Asociado a Receptor de TNF/inmunología , Animales , Rhabdoviridae/inmunología , Pez CebraRESUMEN
Accurate control of innate immune responses is required to eliminate invading pathogens and simultaneously avoid autoinflammation and autoimmune diseases. Here, we demonstrate that arginine monomethylation precisely regulates the mitochondrial antiviral-signaling protein (MAVS)-mediated antiviral response. Protein arginine methyltransferase 7 (PRMT7) forms aggregates to catalyze MAVS monomethylation at arginine residue 52 (R52), attenuating its binding to TRIM31 and RIG-I, which leads to the suppression of MAVS aggregation and subsequent activation. Upon virus infection, aggregated PRMT7 is disabled in a timely manner due to automethylation at arginine residue 32 (R32), and SMURF1 is recruited to PRMT7 by MAVS to induce proteasomal degradation of PRMT7, resulting in the relief of PRMT7 suppression of MAVS activation. Therefore, we not only reveal that arginine monomethylation by PRMT7 negatively regulates MAVS-mediated antiviral signaling in vitro and in vivo but also uncover a mechanism by which PRMT7 is tightly controlled to ensure the timely activation of antiviral defense.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Arginina/metabolismo , Interacciones Huésped-Patógeno/fisiología , Inmunidad Innata/fisiología , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Proteína 58 DEAD Box/metabolismo , Fibroblastos/virología , Células HEK293 , Herpes Simple/inmunología , Herpes Simple/metabolismo , Herpes Simple/virología , Humanos , Metilación , Ratones , Ratones Noqueados , Alcamidas Poliinsaturadas , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/inmunología , Receptores Inmunológicos/metabolismo , Infecciones por Respirovirus/inmunología , Infecciones por Respirovirus/metabolismo , Infecciones por Respirovirus/virología , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Ovarian tumor domain-containing 6B (OTUD6B) belongs to the OTU deubiquitylating enzyme family. In this study, we report that zebrafish otud6b is induced upon viral infection, and overexpression of otud6b suppresses cellular antiviral response. Disruption of otud6b in zebrafish increases the survival rate upon spring viremia of carp virus and grass carp reovirus exposure. Further assays indicate that otud6b interacts with irf3 and irf7 and diminishes traf6-mediated K63-linked polyubiquitination of irf3 and irf7. In addition, the OTU domain is required for otud6b to repress IFN-1 activation and K63-linked polyubiquitination of irf3 and irf7. Moreover, otud6b also attenuates tbk1 to bind to irf3 and irf7, resulting in the impairment of irf3 and irf7 phosphorylation. This study provides, to our knowledge, novel insights into otud6b function and sheds new lights on the regulation of irf3 and irf7 by deubiquitination in IFN-1 signaling.
Asunto(s)
Carpas/inmunología , Factor 3 Regulador del Interferón/inmunología , Factores Reguladores del Interferón/inmunología , Lisina/inmunología , Viremia/inmunología , Proteínas de Pez Cebra/inmunología , Animales , Carpas/virología , Línea Celular , Ubiquitinación , Viremia/virología , Pez Cebra , Proteínas de Pez Cebra/genéticaRESUMEN
Burkholderia pseudomallei is a zoonotic pathogen that usually affects patients' lungs and causes serious melioidosis. The interaction of B. pseudomallei with its hosts is complex, and cellular response to B. pseudomallei infection in humans still remains to be elucidated. In this study, transcriptomic profiling of B. pseudomallei-infected human lung epithelial A549 cells was performed to characterize the cellular response dynamics during the early infection (EI) stage. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed by using the online databases DAVID 6.8 and KOBAS 3.0. Real-time quantitative PCR and western blot were used for validation experiments. Compared with the negative control group (NC), a set of 36 common genes varied over time with a cut-off level of 1.5-fold change, and a P-value < 0.05 was identified. Bioinformatics analysis indicated that the PERK-mediated unfolded protein response (UPR) was enriched as the most noteworthy biological process category, which was enriched as a branch of UPR in the signaling pathway of protein processing in the endoplasmic reticulum. Other categories, such as inflammatory responses, cell migration, and apoptosis, were also focused. The molecular chaperone Bip (GRP78), PERK, and PERK sensor-dependent phosphorylation of eIF2α (p-eIF2α) and ATF4 were verified to be increasing over time during the EI stage, suggesting that B. pseudomallei infection activated the PERK-mediated UPR in A549 cells. Collectively, these results provide important initial insights into the intimate interaction between B. pseudomallei and lung epithelial cells, which can be further explored toward the elucidation of the cellular mechanisms of B. pseudomallei infections in humans.
RESUMEN
The hypoxia-inducible factors 1α and 2α (HIF1α and HIF2α) are master regulators of the cellular response to O2. In addition to HIF1α and HIF2α, HIF3α is another identified member of the HIFα family. Even though the question of whether some HIF3α isoforms have transcriptional activity or repressive activity is still under debate, it is evident that the full length of HIF3α acts as a transcription factor. However, its function in hypoxia signaling is largely unknown. Here, we show that loss of hif3a in zebrafish reduced hypoxia tolerance. Further assays indicated that erythrocyte number was decreased because red blood cell maturation was impeded by hif3a disruption. We found that gata1 expression was downregulated in hif3a null zebrafish, as were several hematopoietic marker genes, including alas2, band3, hbae1, hbae3 and hbbe1 Hif3α recognized the hypoxia response element located in the promoter of gata1 and directly bound to the promoter to transactivate gata1 expression. Our results suggested that hif3a facilities hypoxia tolerance by modulating erythropoiesis via gata1 regulation.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Eritrocitos/metabolismo , Eritropoyesis , Factor de Transcripción GATA1/metabolismo , Hipoxia/metabolismo , Proteínas de Pez Cebra/metabolismo , Pez Cebra/metabolismo , Animales , Antígenos de Diferenciación/biosíntesis , Antígenos de Diferenciación/genética , Proteínas Reguladoras de la Apoptosis/genética , Regulación hacia Abajo , Eritrocitos/patología , Factor de Transcripción GATA1/genética , Hipoxia/genética , Hipoxia/patología , Elementos de Respuesta , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
Arginine methylation catalyzed by protein arginine methyltransferases (PRMT) is a common post-translational modification in histone and nonhistone proteins, which regulates many cellular functions. Protein arginine methyltransferase 3 (prmt3), a type I arginine methyltransferase, has been shown to carry out the formation of stable monomethylarginine as an intermediate before the establishment of asymmetric dimethylarginine. To date, however, the role of PRMT3 in antiviral innate immunity has not been elucidated. This study showed that zebrafish prmt3 was upregulated by virus infection and that the overexpression of prmt3 suppressed cellular antiviral response. The PRMT3 inhibitor, SGC707, enhanced antiviral capability. Consistently, prmt3-null zebrafish were more resistant to Spring Viremia of Carp Virus (SVCV) and Grass Carp Reovirus (GCRV) infection. Further assays showed that the overexpression of prmt3 diminished the phosphorylation of irf3 and prmt3 interacted with rig-i. In addition, both zinc-finger domain and catalytic domain of prmt3 were required for the suppressive function of prmt3 on IFN activation. Our findings suggested that zebrafish prmt3 negatively regulated the antiviral responses, implicating the vital role of prmt3-or even arginine methylation-in antiviral innate immunity.
Asunto(s)
Antivirales/inmunología , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/inmunología , Pez Cebra/genética , Pez Cebra/inmunología , Animales , Células Cultivadas , Histonas/genética , Histonas/inmunología , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Isoquinolinas/inmunología , Metilación , Fosforilación/genética , Fosforilación/inmunología , Procesamiento Proteico-Postraduccional/genética , Procesamiento Proteico-Postraduccional/inmunología , Rhabdoviridae/inmunología , Infecciones por Rhabdoviridae/genética , Infecciones por Rhabdoviridae/inmunología , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , Virosis/genética , Virosis/inmunología , Virosis/virología , Pez Cebra/virología , Dedos de Zinc/genética , Dedos de Zinc/inmunologíaRESUMEN
RLR-mediated type I IFN production plays a pivotal role in innate antiviral immune responses, where the signaling adaptor MAVS is a critical determinant. Here, we show that MAVS is a physiological substrate of SIRT5. Moreover, MAVS is succinylated upon viral challenge, and SIRT5 catalyzes desuccinylation of MAVS. Mass spectrometric analysis indicated that Lysine 7 of MAVS is succinylated. SIRT5-catalyzed desuccinylation of MAVS at Lysine 7 diminishes the formation of MAVS aggregation after viral infection, resulting in the inhibition of MAVS activation and leading to the impairment of type I IFN production and antiviral gene expression. However, the enzyme-deficient mutant of SIRT5 (SIRT5-H158Y) loses its suppressive role on MAVS activation. Furthermore, we show that Sirt5-deficient mice are resistant to viral infection. Our study reveals the critical role of SIRT5 in limiting RLR signaling through desuccinylating MAVS.