Peroxisomes are signaling patforms for antiviral innate immunity
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE21215 | GEO | 2010/11/04
SECONDARY ACCESSION(S): PRJNA126311
REPOSITORIES: GEO
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Project description:Analysis of the transcriptional response of mouse embryonic fibroblasts to reovirus infection. The hypothesis tested was that both peroxisomal and mitochondrial MAVS is capable of inducing the expression of antiviral genes. mRNA isolated from MAVS-expressing cells after infection for various times with reovirus
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Project description:Detection of viral RNA in the cytosol of infected cells depends on RIG-I-lilke recptors that use MAVS as an adapter protein to activate antiviral gene expression. MAVS is tail-anchored on mitochondria, mitochondria-associated membranes and peroxisomes. As peroxisomal membrane proteins can be mistargeted to mitochondria in the absence of peroxisomes, we hypothesized that MAVS-dependent antiviral gene expression is activated more efficiently in this instance. Pex19 deficient skin firoblasts derived from a Zellweger syndrome patient lack peroxisomes. We introduced wild type Pex19 into these cells to restore peroxisome formation and assessed alterations in the gene expression profile of these cells after reovirus infection. 6 samples: 9 and 16 hrs after reovirus infection at an MOI of 100 total RNA was extracted from Pex19 reconstituted and deficient cell lines. Gene expression data was compared to uninfected cells.
2014-04-15 | E-GEOD-56783 | biostudies-arrayexpress
Project description:Detection of viral RNA in the cytosol of infected cells depends on RIG-I-lilke recptors that use MAVS as an adapter protein to activate antiviral gene expression. MAVS is tail-anchored on mitochondria, mitochondria-associated membranes and peroxisomes. As peroxisomal membrane proteins can be mistargeted to mitochondria in the absence of peroxisomes, we hypothesized that MAVS-dependent antiviral gene expression is activated more efficiently in this instance. Pex19 deficient skin firoblasts derived from a Zellweger syndrome patient lack peroxisomes. We introduced wild type Pex19 into these cells to restore peroxisome formation and assessed alterations in the gene expression profile of these cells after reovirus infection.
2014-04-15 | GSE56783 | GEO
Project description:Innate immunity serves as the primary defense against viral and microbial infections in humans. Among its components, retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are well-characterized intracellular pattern-recognition proteins that trigger innate immune responses upon viral infection. However, the precise influence of cellular metabolites, especially fatty acids, on the regulation of RLR-mediated antiviral innate immunity remains largely elusive. Here, through screening a metabolite library, palmitic acid (PA) has been identified as a crucial metabolite responsible for modulating antiviral infections. Mechanistically, PA induces the palmitoylation of MAVS, leading to MAVS aggregation and subsequent activation, thereby enhancing the innate immune response against viral infections. Functionally, the enzyme palmitoyl-transferase ZDHHC24 plays a key role in catalyzing the palmitoylation of MAVS at both C46 and C79 residues, thereby facilitating the transduction of RLR-mediated TBK1-IRF3-IFN signaling pathway, particularly under conditions of PA stimulation or high-fat diet feeding. Conversely, the absence of ZDHHC24 significantly attenuates virus-induced innate immune responses in both cells and mice. Moreover, APT2 counteracts with ZDHHC24 to de-palmitoylate MAVS, thus inhibiting the antiviral response. Consequently, inhibition of APT2 using compounds like ML349 effectively reverses MAVS palmitoylation and activation in response to antiviral infections. These findings underscore the critical role of PA and ZDHHC24 in regulating antiviral innate immunity through MAVS palmitoylation, and suggest potential therapeutic strategies for combating viral infections, such as enhancing PA intake or specifically targeting APT2.
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Project description:Peroxisomes have long been established to play a central role in regulating various metabolic activities in mammalian cells. These organelles act in concert with mitochondria to control the metabolism of lipids and reactive oxygen species. However, while mitochondria have emerged as an important site of antiviral signal transduction, a role for peroxisomes in immune defense is unknown. Here, we report that the RIG-I-like receptor (RLR) adaptor protein MAVS is located on peroxisomes and mitochondria. We find that peroxisomal and mitochondrial MAVS act sequentially to create an antiviral cellular state. Upon viral infection, peroxisomal MAVS induces the rapid interferon-independent expression of defense factors that provide short-term protection, whereas mitochondrial MAVS activates an interferon-dependent signaling pathway with delayed kinetics, which amplifies and stabilizes the antiviral response. The interferon regulatory factor IRF1 plays a crucial role in regulating MAVS-dependent signaling from peroxisomes. These results establish that peroxisomes are an important site of antiviral signal transduction.
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Project description:MicroRNAs (miRNAs) are short non-coding RNAs act as a suppressor of multiple genes and it is known that miRNAs link to numerous biological functions. Mitochondria act as a platform for innate immune response against RNA viruses via a mitochondrial outer membrane protein, MAVS. Here we report miR-302b and miR-372 involve in mitochondrial-mediated antiviral response. These miRNAs were upregulated by viral infection and influenced not only the production of type I interferon and inflammatory cytokines, but also mitochondrial function. Furthermore, we revealed that these phenotypes were induced by changing several mitochondrial genes expression. miR-302b induced mitochondrial fragmentation by changing gene expression related to mitochondrial dynamics to regulate Drp1 activity. Indeed, downregulation of SLC25A12 by miR-302b suppressed antiviral responses via inhibiting the MAVS activation directly. We first propose that miR-302b and miR-372 act as negative regulator of antiviral response by affecting mitochondrial function to inhibit excessive innate immune response.
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Project description:Pattern recognition receptors (PRRs)-mediated innate immune responses are critical for host defense against microbial pathogens including RNA/DNA viruses. A growing number of coding genes and genes originally defined as non-coding RNAs (ncRNAs) are found to encode short peptides or proteins, named microproteins. However, the landscape of microproteins in responsive to virus infection and the functions of these microproteins remain uncharacterized. Here, we systematically identified microproteins, both from coding and non-coding genes, that are responsive to Vesicular Stomatitis Virus (VSV) infection. Among which, a highly conserved, endoplasmic reticulum (ER) membrane-localized microprotein, , MAVI1 (microprotein in antiviral immunity 1), was found to interact with mitochondrial localized MAVS protein, inhibiting the aggregation of MAVS and the activation of downstream type I interferon (IFN) signaling pathway. The critical role of MAVI1 was highlighted that viral infection was significantly attenuated and survival rate was significantly increased in Mavi1 knockout mice in vivo. A peptide inhibitor targeting the interaction between MAVI1 and MAVS is potent in activating the type I IFN signaling and defending viral infection both in vitro and in vivo. Our findings uncovered that microproteins could play critical roles in regulating antiviral innate immune responses via cross-organelle interaction, and targeting microproteins might represent a potential therapeutic avenue for treating viral infection in clinic.
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Project description:We investigated the roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus (DENV). Double-deficient Irf-3-/-7-/- mice infected with the DENV2 strain S221 possessed 1,000-150,000 fold higher levels of viral RNA than wild-type and single-deficient mice 24 hours after infection; however, they remained resistant to lethal infection. IFN-α/β was induced similarly in wild-type and Irf-3-/- mice post DENV infection, whereas in the Irf-7-/- and Irf-3-/-7-/- mice, significantly low levels of IFN-α/β expression was observed within 24 hours post-infection. IFN-stimulated gene (ISG) induction was also delayed in Irf-3-/-7-/- mice relative to wild-type and single-deficient mice. In particular, Cxcl10 and Ifnα2 were rapidly induced independently of both IRF-3 and IRF-7 in the Irf-3-/-7-/- mice with DENV infection. Higher levels of serum IFN-γ, IL-6, CXCL10, IL-8, IL-12 p70, and TNF were also observed in Irf-3-/-7-/- mice 24 hours after infection, at which time point viral titers peaked and started to be cleared. Antibody-mediated blockade experiments revealed that IFN-γ, CXCL10, and CXCR3 function to restrict DENV replication in Irf-3-/-7-/- mice. Additionally, the ISGs Cxcl10, Ifit1, Ifit3, and Mx2 can be induced via an IRF-3- and IRF-7-independent pathway that does not involve IFN-γ signaling for protection against DENV. Collectively, these results demonstrate that IRF-3 and IRF-7 are redundant, albeit IRF-7 plays a more important role than IRF-3 in inducing the initial IFN-α/β response; only the combined actions of IRF-3 and IRF-7 are necessary for efficient control of early DENV infection; and the late, IRF-3- and IRF-7-independent pathway contributes to anti-DENV immunity. To identify the antiviral genes that are controlled by IRF-3 and IRF-7 signaling during DENV infection, we examined a panel of ISG expression in the spleens of wild-type, Irf-3-/-, Irf-7-/- and Irf-3-/-7-/- mice at 12 or 24 hours after DENV infection using a quantitative PCR array kit. The fold changes in expression of 55 genes from infected mice were normalized to that of strain-matched naïve mice.
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