Oxygen enhances antiviral innate immunity through maintenance of EGLN1-catalyzed proline hydroxylation of IRF3.

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.

Integrated analysis reveals the regulatory mechanism of the neddylation inhibitor MLN4924 on the metabolic dysregulation in rabbit granulosa cells.

BACKGROUND: Neddylation, an important post-translational modification (PTM) of proteins, plays a crucial role in follicular development. MLN4924 is a small-molecule inhibitor of the neddylation-activating enzyme (NAE) that regulates various biological processes. However, the regulatory mechanisms of neddylation in rabbit ovarian cells have not been emphasized. Here, the transcriptome and metabolome profiles in granulosa cells (GCs) treated with MLN4924 were utilized to identify differentially expressed genes, followed by pathway analysis to precisely define the altered metabolisms. RESULTS: The results showed that 563 upregulated and 910 downregulated differentially expressed genes (DEGs) were mainly enriched in pathways related to cancer, cell cycle, PI3K-AKT, progesterone-mediated oocyte maturation, and PPAR signaling pathway. Furthermore, we characterized that MLN4924 inhibits PPAR-mediated lipid metabolism, and disrupts the cell cycle by promoting the apoptosis and proliferation of GCs. Importantly, we found the reduction of several metabolites in the MLN4924 treated GCs, including glycerophosphocholine, arachidic acid, and palmitic acid, which was consistent with the deregulation of PPAR signaling pathways. Furthermore, the increased metabolites included 6-Deoxy-6-sulfo-D-glucono-1,5-lactone and N-Acetyl-D-glucosaminyldiphosphodolichol. Combined with transcriptome data analyses, we identified genes that strongly correlate with metabolic dysregulation, particularly those related to glucose and lipid metabolism. Therefore, neddylation inhibition may disrupt the energy metabolism of GCs. CONCLUSIONS: These results provide a foundation for in-depth research into the role and molecular mechanism of neddylation in ovary development.

Zebrafish spop promotes ubiquitination and degradation of mavs to suppress antiviral response via the lysosomal pathway.

Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) signaling pathways are required to be tightly controlled to initiate host innate immune responses. Fish mitochondrial antiviral signaling (mavs) is a key determinant in the RLR pathway, and its ubiquitination is associated with mavs activation. Here, we identified the zebrafish E3 ubiquitin ligase Speckle-type BTB-POZ protein (spop) negatively regulates mavs-mediated the type I interferon (IFN) responses. Consistently, overexpression of zebrafish spop repressed the activity of IFN promoter and reduced host ifn transcription, whereas knockdown spop by small interfering RNA (siRNA) transfection had the opposite effects. Accordingly, overexpression of spop dampened the cellular antiviral responses triggered by spring viremia of carp virus (SVCV). A functional domain assay revealed that the N-terminal substrate-binding MATH domain regions of spop were necessary for IFN suppression. Further assays indicated that spop interacts with mavs through the C-terminal transmembrane (TM) domain of mavs. Moreover, zebrafish spop selectively promotes K48-linked polyubiquitination and degradation of mavs through the lysosomal pathway to suppress IFN expression. Our findings unearth a post-translational mechanism by which mavs is regulated and reveal a role for spop in inhibiting antiviral innate responses.

Characteristics of conserved microRNAome and their evolutionary adaptation to regulation of immune defense functions in the spleen of silver carp and bighead carp.

Immune defense functions of silver carp (Hypophthalmichthys molitrix) and bighead carp (Hypophthalmichthys nobilis) have shown obvious evolutionary divergence. MiRNAs participate in the fine regulation of immune function. However, the evolutionary adaptation of miRNAs in the regulation of immune defense function is still poorly understood in silver carp and bighead carp. Here, small RNA libraries were constructed from the spleen tissue of one-year-old and three-year-old healthy silver carp and bighead carp, 424 and 422 known conserved miRNAs were respectively identified from the spleen of silver carp and bighead carp by bioinformatic analysis, which 398 were shared between the two species. These conserved miRNAs showed highly similar expression patterns between silver carp and bighead carp, but the abundance in spleen varied greatly in different species. Family analysis showed that miRNA families including mir-8, mir-7, mir-23, mir-338, mir-30, mir-27, mir-221, mir-19, mir-181, mir-17, mir-15, mir-148, mir-130, mir-10 and let-7 were the main miRNAs in the spleen of silver carp and bighead carp. 27 and 51 significant differentially expressed (SDE) miRNAs were identified from silver carp and bighead carp, respectively. Evolution analysis for the predicted target genes of SDE-miRNAs showed that ten biological processes such as blood coagulation, cell adhesion mediated by integrin and adaptive immune response were positively selected. In addition, immune genes including TLR3, NFATC3, MALT1, B2M, GILT and MHCII were positively selected only in silver carp, and they were specifically targeted by the SDE-miRNAs including miR-9-5p, miR-196a-5p, miR-375, miR-122, miR-722, miR-132-3p, miR-727-5p, miR-724, miR-19d-5p and miR-138-5p, respectively. PLA2G4 in Fc epsilon RI signaling pathway was positively selected only in bighead carp and was specifically targeted by the SDE-miRNAs including miR-222b, miR-22b-5p, miR-15c, miR-146a, miR-125c-3p, miR-221-5p, miR-2188-5p, miR-142a-3p, miR-212, miR-138-5p and miR-15b-5p. In particular, SDE-miRNAs such as miR-144-3p, miR-2188-3p, miR-731, miR-363-3p and miR-218b could simultaneously target multiple evolutionarily differentiated immune-related genes. These results indicated that in the spleen of silver carp and bighead carp, conserved miRNAs have obvious evolutionary adaptations in the regulation of immune defense function. The results of this study can provide valuable resources for further revealing themechanism of miRNA in the formation of resistance traits evolution between silver carp and bighead carp.

Deletion of prolyl hydroxylase domain-containing enzyme 3 (phd3) in zebrafish facilitates hypoxia tolerance.

Prolyl hydroxylase domain (PHD)-containing enzyme 3 (PHD3) belongs to the Caenorhabditis elegans gene egl-9 family of prolyl hydroxylases. PHD3 catalyzes proline hydroxylation of hypoxia-inducible factor α (HIF-α) and promotes HIF-α proteasomal degradation through coordination with the pVHL complex under normoxic conditions. However, the relationship between PHD3 and the hypoxic response is not well understood. In this study, we used quantitative real-time PCR assay and O-dianisidine staining to characterize the hypoxic response in zebrafish deficient in phd3. We found that the hypoxia-responsive genes are upregulated and the number of erythrocytes was increased in phd3-null zebrafish compared with their wild-type siblings. On the other hand, we show overexpression of phd3 suppresses HIF-transcriptional activation. In addition, we demonstrate phd3 promotes polyubiquitination of zebrafish hif-1/2α proteins, leading to their proteasomal degradation. Finally, we found that compared with wild-type zebrafish, phd3-null zebrafish are more resistant to hypoxia treatment. Therefore, we conclude phd3 has a role in hypoxia tolerance. These results highlight the importance of modulation of the hypoxia signaling pathway by phd3 in hypoxia adaptation.

Screening and Stability Analysis of Reference Genes for Gene Expression Normalization in Hybrid Yellow Catfish (Pelteobagrus fulvidraco ♀ × Pelteobagrus vachelli ♂) Fed Diets Containing Different Soybean Meal Levels.

In this study, we screened the expression stability of six reference genes (18S rRNA, ß-actin, GAPDH, EF1a, B2M, and HPRT1) in hybrid yellow catfish (n = 6), considering the SBM levels, sampling time points, and different tissues. Four different statistical programs, BestKeeper, NormFinder, Genorm, and Delta Ct, combined with a method that comprehensively considered all results, were used to evaluate the expression stability of these reference genes systematically. The results showed that SBM levels significantly impacted the expression stability of most of the reference genes studied and that this impact was time-, dose-, and tissue-dependent. The expression stability of these six reference genes varied depending on tissue, sampling time point, and SBM dosage. Additionally, more variations were found among different tissues than among different SBM levels or sampling time points. Due to its high expression, 18S rRNA was excluded from the list of candidate reference genes. ß-actin and GAPDH in the liver and ß-actin, HPRT1 and EF1a in the intestine were the most stable reference genes when SBM levels were considered. HPRT1, and EF1a in tissues sampled at 2 W and EF1a and ß-actin in tissues sampled at 4 and 6 W were proposed as two stable reference genes when different tissues were considered. When the sampling time points were considered, ß-actin, EF1a, and HPRT1 were the top three stable reference genes in the intestine. In contrast, ß-actin and B2M are the most stable reference genes in the liver. In summary, ß-actin, EF1a, and HPRT1 were the more stable reference genes in this study. The stability of reference genes depends on the tissues, sampling time points, and SBM diet levels in hybrid yellow catfish. Therefore, attention should be paid to these factors before selecting suitable reference genes for normalizing the target genes.

Zebrafish sirt5 Negatively Regulates Antiviral Innate Immunity by Attenuating Phosphorylation and Ubiquitination of mavs.

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.

Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling.

Disruption of androgen signaling is known to cause testicular malformation and defective spermatogenesis in zebrafish. However, knockout of cyp17a1, a key enzyme responsible for the androgen synthesis, in ar-/- male zebrafish paradoxically causes testicular hypertrophy and enhanced spermatogenesis. Because Cyp17a1 plays key roles in hydroxylation of pregnenolone and progesterone (P4), and converts 17α-hydroxypregnenolone to dehydroepiandrosterone and 17α-hydroxyprogesterone to androstenedione, we hypothesize that the unexpected phenotype in cyp17a1-/-;androgen receptor (ar)-/- zebrafish may be mediated through an augmentation of progestin/nuclear progestin receptor (nPgr) signaling. In support of this hypothesis, we show that knockout of cyp17a1 leads to accumulation of 17α,20ß-dihydroxy-4-pregnen-3-one (DHP) and P4. Further, administration of progestin, a synthetic DHP mimetic, is sufficient to rescue testicular development and spermatogenesis in ar-/- zebrafish, whereas knockout of npgr abolishes the rescue effect of cyp17a1-/- in the cyp17a1-/-;ar-/- double mutant. Analyses of the transcriptomes among the mutants with defective testicular organization and spermatogenesis (ar-/-, ar-/-;npgr-/- and cyp17a-/-;ar-/-;npgr-/-), those with normal phenotype (control and cyp17a1-/-), and rescued phenotype (cyp17a1-/-;ar-/-) reveal a common link between a downregulated expression of insl3 and its related downstream genes in cyp17a-/-;ar-/-;npgr-/- zebrafish. Taken together, our data suggest that genetic or pharmacological augmentation of the progestin/nPgr pathway is sufficient to restore testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling.

Zebrafish sirt7 Negatively Regulates Antiviral Responses by Attenuating Phosphorylation of irf3 and irf7 Independent of Its Enzymatic Activity.

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.

The effect of glucocorticoids on mortality in severe COVID-19 patients: Evidence from 13 studies involving 6612 cases.

BACKGROUND: Since the start of the coronavirus disease 2019 (COVID-19) pandemic, there is an urgent need for effective therapies for patients with COVID-19. In this study, we aimed to assess the therapeutic efficacy of glucocorticoids in severe COVID-19. METHODS: A systematic literature search was performed across PubMed, Web of Science, EMBASE, and the Cochrane Library (up to June 26, 2021). The literature investigated the outcomes of interest were mortality and invasive mechanical ventilation. RESULTS: The search identified 13 studies with 6612 confirmed severe COVID-19 patients. Our meta-analysis found that using glucocorticoids could significantly decrease COVID-19 mortality (hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.45-0.79, P < .001), relative to non-use of glucocorticoids. Meanwhile, using glucocorticoids also could significantly decrease the risk of progression to invasive mechanical ventilation for severe COVID-19 patients (HR = 0.69, 95% CI 0.58-0.83, P < .001). Compared with using dexamethasone (HR = 0.68, 95% CI 0.50-0.92, P = .012), methylprednisolone use had a better therapeutic effect for reducing the mortality of patients (HR = 0.35, 95% CI 0.19-0.64, P = .001). CONCLUSION: The result of this meta-analysis showed that using glucocorticoids could reduce mortality and risk of progression to invasive mechanical ventilation in severe COVID-19 patients.

Zebrafish otud6b Negatively Regulates Antiviral Responses by Suppressing K63-Linked Ubiquitination of irf3 and irf7.

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.

An acute gastroenteritis outbreak associated with breakfast contaminated with norovirus by asymptotic food handler at a kindergarten in Shenzhen, China.

BACKGROUND: An outbreak of acute gastroenteritis occurred in a kindergarten located Shenzhen City on March 4, 2018. We were invited to investigate to the risk factors associated with this outbreak. METHODS: We conducted retrospective cohort-studies on three different groups of subjects in order to figure out the difference of incidence of acute gastroenteritis among subjects of different activities on March 2: group one consisted of people who attended the Lantern festival activities; group two consisted of children and employees who ate breakfast and bread provided by the kindergarten; and groups three consisted of children and employees who did not eat breakfast or bread provided by the kindergarten. Fecal, anal swabs, dishware swabs and hand swabs specimens were collected in the study. Bacteria known to cause acute gastroenteritis were cultured. Viruses associated with acute gastroenteritis were tested using real-time PCR. Capsid gene fragment of 557 bp of norovirus was amplified and sequenced. The phylogenetic tree was constructed with MEGA 7.0 using neighbor-joining method based on capsid gene fragment of norovirus. RESULTS: A total of 143 suspected cases were identified in this outbreak. Diarrhea happened more often in adults than in children while emesis and bellyache were more frequently found in children than in adults. Higher AGE incidence was observed in group 2, children and employees who had breakfast in the kindergarten on March 2, as well as in group 3, and among employees who eating bread involved in breakfast provided on March 2. Five anal swab specimens were positive for norovirus. All noroviruses belongs to group II.3 and have an identity more than 99%. CONCLUSION: A chef, as an asymptomatic carrier with norovirus, was the infectious resource in this outbreak. He contaminated breakfast food provided on March 2. Although morning check is implemented in kindergartens of China, employees are often excluded in morning check. Our finding highlights the importance of morning check covering employees and periodical training for cooks.

Zebrafish Nedd8 facilitates ovarian development and the maintenance of female secondary sexual characteristics via suppression of androgen receptor activity.

Nedd8 is a ubiquitin-like protein that covalently conjugates to target proteins through neddylation. In addition to cullin-RING ligases, neddylation also modifies non-cullin proteins to regulate protein activity, stability and localization. However, the roles of NEDD8 remain largely unknown in vivo Here, we found that loss of nedd8 in female zebrafish led to defects in oogenesis, disrupted oocyte maturation and stimulated growth of the breeding tubercles (BTs) on the pectoral fins. The BTs are normally present in males, not females. However, the loss of one copy of ar can partially rescue the phenotypes displayed by nedd8-null female zebrafish. Further assays indicated that Nedd8 conjugates to Ar and Ar is neddylated at lysine 475 and lysine 862. Moreover, Nedd8 conjugation efficiently suppressed Ar transcriptional activity. Lysine 862 (K862) of Ar is the key site modified by neddylation to modulate Ar transcriptional activity. Thus, our results not only demonstrated that Nedd8 modulates ovarian maturation and the maintenance of female secondary sexual characteristics of female zebrafish in vivo, but also indicated that androgen signaling is strictly regulated by nedd8.

TET is targeted for proteasomal degradation by the PHD-pVHL pathway to reduce DNA hydroxymethylation.

Hypoxia-inducible factors are heterodimeric transcription factors that play a crucial role in a cell's ability to adapt to low oxygen. The von Hippel-Lindau tumor suppressor (pVHL) acts as a master regulator of HIF activity, and its targeting of prolyl hydroxylated HIF-α for proteasomal degradation under normoxia is thought to be a major mechanism for pVHL tumor suppression and cellular response to oxygen. Whether pVHL regulates other targets through a similar mechanism is largely unknown. Here, we identify TET2/3 as novel targets of pVHL. pVHL induces proteasomal degradation of TET2/3, resulting in reduced global 5-hydroxymethylcytosine levels. Conserved proline residues within the LAP/LAP-like motifs of these two proteins are hydroxylated by the prolyl hydroxylase enzymes (PHD2/EGLN1 and PHD3/EGLN3), which is prerequisite for pVHL-mediated degradation. Using zebrafish as a model, we determined that global 5-hydroxymethylcytosine levels are enhanced in vhl-null, egln1a/b-double-null, and egln3-null embryos. Therefore, we reveal a novel function for the PHD-pVHL pathway in regulating TET protein stability and activity. These data extend our understanding of how TET proteins are regulated and provide new insight into the mechanisms of pVHL in tumor suppression.

Risk factors for severe hand, foot, and mouth disease infected with Coxsackievirus A6: A hospital-based case-control study.

Coxsackievirus 6 (CV-A6) has been emerging as another predominant serotype for severe hand, foot, and mouth disease (HFMD) in China, after the introduction of enterovirus 71 inactivated vaccine (EV71 vaccine) for 3 years. Data on the risk factors for severe HFMD infected with CV-A6 are limited. We interviewed the caregivers to collected data on HFMD patients who sought medical care in the People's Hospital of Baoan district, Shenzhen, from 2015 to 2017. Totally, 131 severe patients were frequency-matched by age and gender with 174 mild patients infected with CV-A6. Univariable and multivariable logistic regression analyses were conducted to analyze the risk factors for severe CV-A6 HFMD. The average age was 20.62 ± 14.18 months and 20.52 ± 12.76 months for severe and mild patients, respectively. Multivariate analyses indicated complications at birth (odds ratio [OR], 4.18; 95% confidence interval [CI]: 1.64-10.63), peak body temperature over 39°C (OR, 4.04; 95% CI: 2.29-7.10) and first-born child (OR, 2.17; 95% CI: 1.27-3.70) increased the risk of severe HFMD infected with CV-A6. Breastfeeding (OR, 0.52; 95% CI: 0.32-0.87), and washing hands after playing frequently (OR, 0.58; 95% CI: 0.34-0.97) were negatively associated with severe illness. Compared with HFMD with infection of EV-A71, complications at birth and first-born child were newly found to be associated with severe illness in HFMD patients infected with CV-A6.

Zebrafish phd3 Negatively Regulates Antiviral Responses via Suppression of Irf7 Transactivity Independent of Its Prolyl Hydroxylase Activity.

Prolyl hydroxylase domain (PHD)-containing enzyme 3 belongs to the Caenorhabditis elegans gene egl-9 family of prolyl hydroxylases, which has initially been revealed to hydroxylate hypoxia-inducible factor α (HIF-α) and mediate HIF-α degradation. In addition to modulating its target function by hydroxylation, PHD3 has been also shown to influence its binding partners' function independent of its prolyl hydroxylase activity. In this study, we report that overexpression of zebrafish phd3 suppresses cellular antiviral response. Moreover, disruption of phd3 in zebrafish increases the survival rate upon spring viremia of carp virus exposure. Further assays indicate that phd3 interacts with irf7 through the C-terminal IRF association domain of irf7 and diminishes K63-linked ubiquitination of irf7. However, the enzymatic activity of phd3 is not required for phd3 to inhibit irf7 transactivity. This study provides novel insights into phd3 function and sheds new light on the regulation of irf7 in retinoic acid-inducible gene I-like receptor signaling.

Genome-wide association study identifies TPH2 variant as a novel locus for severe CV-A6-associated hand, foot, and mouth disease in Han Chinese.

BACKGROUND: Little is known about the association between genetic susceptibility and the severity of hand, foot, and mouth disease (HFMD) infected with coxsackievirus A6 (CV-A6). METHODS: Three hundred and sixty-four CV-A6 HFMD patients were enrolled, including 115 severe and 249 mild patients. A genome-wide association study (GWAS) was performed involving eight DNA pools of 115 severe and 115 mild CV-A6 HFMD patients pair-matched by age and gender. Differences in relative allele signal scores of SNPs in Illumina Human OmniZhongHua-8 BeadChips were compared between the two groups. The tag SNPS for potentially functional SNPs or their high linked SNPs were selected for individual genotyping in all 364 patients and assessed for their associations with severe CV-A6 HFMD using multivariable logistic regression analyses. RESULTS: The top 30 significant SNPs obtained from pooled DNA GWAS analysis were checked for biological functions and their high linkage disequilibrium (LD) SNPs. Four tag SNPs (rs1558206, rs6927647, rs9375728 and rs10879355) were selected for further individual genotyping in 364 CV-A6 patients. Only SNP rs10879355 was associated with severe CV-A6 HFMD, with CC genotype having a greater risk of severe illness than TT+TC genotypes (OR=2.48, 95%CI: 1.34, 4.56). SNP rs4290270 is in complete LD with rs10879355 in Chinese Han children. CONCLUSIONS: This is the first report that one potentially functional SNP rs4290270 in the TPH2 gene may be associated with the risk of severe CV-A6 HFMD.

SIRT5 impairs aggregation and activation of the signaling adaptor MAVS through catalyzing lysine desuccinylation.

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.