These findings suggested that the morphological changes were not the result of mitochondrial damage. Recent reports have demonstrated that several types of mitochondrial stress cause the release of cytosolic mtDNA from mitochondria, which can trigger antiviral responses [ 22 , 23 ]. We next performed knockdown of sensor molecules for intracellular foreign nucleic acids.
We observed the mitochondrial morphology after MeV infection in MAVS knockdown cells, and found that mitochondrial hyperfusion was the same as in normal control cells S3C Fig. This indicated that the formation of hyperfused mitochondria is a distinct process from that of the assembly of activated MAVS on the outer mitochondrial membrane induced by RNA virus infections [ 25 ].
A luciferase assay driven by type-I interferon stimulated response elements ISRE was measured following MeV infection over a set time course. To prove the direct involvement of mtDNA release in antiviral responses in MeV-infected cells, we used dideoxycytidine ddC , a deoxyribonucleoside analogue that specifically inhibits mtDNA replication [ 28 , 29 ]. B Immunoprecipitation followed by qPCR. Upper left: immunoblot of cell lysate transfected with empty plasmid or plasmid expressing HA-tagged cGAS.
Left: immunoblot of the cell lysate. Upper: Cells were harvested at the indicated time and the luciferase activities were measured. Data are representative of three independent experiments. These data indicated that MeV infection promotes the liberation of mtDNA from mitochondria, which accesses the cytosol to engage in innate immune signaling triggered by cGAS.
To confirm whether the cytosolic release of mtDNA is a consequent of mitochondrial hyperfusion, we first tested artificial defects of mitochondrial hyperfusion by knockdown of mitofusin 1 Mfn1 Fig 3A , which plays a key role in the fusion of mitochondria. Mfn1 depletion induced no apparent hyperfusion but rather fission of mitochondria in MeV-infected cells Fig 3B and 3C. These results showed that mitochondrial hyperfusion and the liberation of mtDNA by MeV infection is conducted by Mfn1.
Previous reports indicated that cellular stress induced by treatment with actinomycin D ActD or UV irradiation promoted mitochondrial hyperfusion, which is also mediated by Mfn1 [ 17 ]. These findings suggested that the mitochondrial fusion involving Mfn1 is required for mtDNA release, but additional process es contribute to mtDNA liberation induced by MeV infection. A Cell lysates analyzed to western blotting. At 16 hpi, mitochondria were stained with MitoTracker.
C Mitochondria morphology of at least 30 cells per condition and in three independent experiments were classified as normal, elongated, or fragmented mitochondrial network. Mitochondria and nuclei were stained 7 h later with MitoTracker and Hoechst, respectively. We next analyzed whether the downregulation of mitochondrial biogenesis characteristically observed in MeV-infected cells is implicated in mtDNA release.
Taken together, these findings suggested that the comprehensive downregulation of mitochondrial biogenesis causes cytosolic release of mtDNA and consequent antiviral priming.
We investigated whether other viruses also induce downregulation of mitochondrial biogenesis. We searched microarray databases or previous reports of related viruses that cause downregulation of host gene expression, in which the list of downregulated genes included enriched mitochondrial protein genes.
Among -ssRNA viruses, respiratory syncytial virus RSV shows significant downregulation of genes encoding mitochondrial proteins after infection the fold-enrichment of mitochondria-related genes was low, but the total number of genes was high Figs 5A and S6 [ 42 ]. We first observed mitochondrial morphology after infection.
Each item in the graph is represented as shown for Fig 1A. Uppermost layers in the list are shown in S6 Fig CPV showed no obvious enrichment in cellular components. Mitochondria were stained with anti COX IV antibody red and virus antigen was stained with antibody against each virus protein green , as described in Materials and Methods. B Quantification of the impact of virus infection on mitochondria morphology.
From these data, we propose that viruses which possess the potential to intrinsically downregulate mitochondrial biogenesis, as seen for MeV, activate cGAS-dependent antiviral responses via the liberation of mtDNA to the cytosol by the hyperfusion of mitochondria. This cascade is considered to be required for full innate antiviral responses against these viruses. These findings uncover a novel host strategy of the defense system for suppressing viral propagation.
Under normal circumstances, the cytoplasm is devoid of DNA. Nevertheless, several recent reports have revealed that mtDNA can gain access to the cytoplasm under certain circumstances of stress or damage, and provoke at least three pathways for innate immune responses; mtDNA acts as a damage-associated molecular pattern in inflammation initiation through direct activation of TLR9, which usually recognizes bacterial DNA [ 48 — 50 ].
Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production, mtDNA can be identified as an intrinsic cellular trigger of antiviral signaling and cellular monitoring of mtDNA homeostasis cooperates with established virus sensing mechanisms. West and colleagues revealed that HSV-1 infection causes mtDNA stress, and induces mitochondrial hyperfusion conducted by Mfn1 [ 24 ], but the detail of this process remains to be elucidated.
Therefore, it is suggested that mtDNA release followed by mitochondrial hyperfusion induced by virus infection is required for undetermined inherent processes, and further studies are required to clarify the phenomenon.
It is speculated that cGAS plays a role in maintaining the basal level of ISG expression, which suppresses virus replication. Intriguingly, recent reports revealed that dengue virus and Zika virus, which belong to the family Flaviviridae, induce mtDNA release into the cytosol, which is captured by cGAS [ 57 , 58 ]. In the present study, we propose that induction of antiviral priming by mtDNA via cGAS is a general response to virus infection, which can lead to the intrinsic downregulation of mitochondrial protein expression.
However, among the viruses we tested, MeV, RSV and MVA, no common viral component or characteristic was found, thus the factor s responsible for mitochondrial downregulation is still unclear. Interestingly, all six viruses in the present study caused the downregulation of expression of over genes; however, SeV, VSV and CPV showed little or no enrichment in gene ontology analysis, indicating that the strategy of downregulation was no operating in these viruses.
By contrast, the other viruses targeted various cellular components in addition to mitochondria, thus they might possess an individual approach for downregulation. It is difficult to clarify comprehensively the inherent mechanism by which the virus targets specific cellular pathways and induces alterations in the host transcriptional regulatory network.
We are currently attempting to depict the whole transcriptional regulatory network of the host after MeV infection using CAGE cap analysis of gene expression with a next generation sequencer and comprehensive analysis of promoter activities across the whole genome.
These high-throughput experiments may uncover the comprehensive host response to virus infection, and will be useful for understanding the whole picture regarding the complexity of virus infection in general.
Antibodies used in this study are described in S1 Table. SeV strain Z was inoculated into day-old embryonated chicken eggs. After 3 days of incubation, the allantoic fluid was harvested and assayed for plaque forming units pfu as described previously [ 60 ]. The virus titer was measured with MDCK cells. Viruses were infected into cells at a multiplicity of infection of 0. Cells were washed twice with fresh culture medium and further incubated for 30 min.
Cells were washed with PBS between each step. Image processing e. Other image processing, such as haze reduction and edge enhancement, was not applied. The mitochondrial network was examined and classified into three distinct categories; normal, fragmented, and elongated morphology.
After 10 h, cells were stained with MitoTracker as described above. From 11 h post-infection, fluorescence images were acquired every 6 min for 20 h using an IX70 laser confocal microscope and the FluoView FV system Olympus, Japan at V for green and V for red.
For relative expression fold , control samples were centered at 1. After washing twice with fresh medium, fluorescence was observed as described above. To measure cytosolic mtDNA, cells were divided into two equal aliquots, and one aliquot served as the total mtDNA described above or the whole cell lysate WCL for western blotting.
The value of the control antibody was subtracted from that of the anti-HA-tag antibody, and the obtained values were used for enrichment analysis. Metal preferences and metallation. Irving, H.
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