RLR-mediated antiviral innate immunity requires oxidative phosphorylation activity

Yoshizumi, Takuma; Imamura, Hiromi; Taku, Tomohiro; Kuroki, Takahiro; Kawaguchi, Atsushı; Ishikawa, Kaori; Nakada, Kazuto; Koshiba, Takumi

doi:10.1038/s41598-017-05808-w

Cited by 48 publications

(47 citation statements)

References 42 publications

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“…Mitochondria are known to play an important role in innate immune responses against RNA viruses [20][21][22][23] . Recognition of cytosolic viral RNA by retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) and their downstream processes have been shown to require the participation of mitochondrial antiviral signaling (MAVS), a mitochondrial outer membrane adaptor protein 20,24,25 .…”

Section: Introductionmentioning

confidence: 99%

Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages

Ahmed

Roy

Jaworski

et al. 2019

Preprint

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Increasing evidence suggests that mitochondria play a critical role in driving innate immune responses against bacteria and viruses. However, it is unclear if differential reprogramming of mitochondrial function contributes to the fine tuning of pathogen specific immune responses. Here, we found that TLR3 and TLR4 engagement on murine bone marrow derived macrophages was associated with differential remodeling of electron transport chain complex expression. This remodeling was associated with differential accumulation of mitochondrial and cytosolic ROS, which were required to support ligand specific inflammatory and antiviral cytokine production.We also found that the magnitude of TLR3, but not TLR4, responses were modulated by glucose availability. Under conditions of low glucose conditions, TLR3 engagement was associated with increased ETC complex III expression, increased mitochondrial and cytosolic ROS and increased inflammatory and antiviral cytokine production. This amplification was selectively reversed by targeting superoxide production from the outer Q-binding site of the ETC complex III. These results suggest that ligand specific modulation of the ETC may act as a rheostat that fine-tunes innate immune responses via mitochondrial ROS production. Modulation of these processes may represent a novel mechanism to modulate the nature as well as the magnitude of antiviral versus inflammatory immune responses.3 Introduction:

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Section: Introductionmentioning

confidence: 99%

Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages

Ahmed

Roy

Jaworski

et al. 2019

Preprint

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“…A recent paper showed that Drp1-dependent mitochondrial dynamic was coupled with oxidative respiration: tubular mitochondria was accompanied with increased oxidative respiration, while fragmented mitochondria achieved the opposite [37]. The oxidative phosphorylation activity was supposed to be required in the RLR innate immune signaling, as SeV-induced IFN production was impaired in cells with oxidative phosphorylation defect, but was restored when the oxidative phosphorylation was recovered [38]. In our study, increased tubular mitochondrial and impaired SeV-induced IFN production was observed in PLA1A knockdown cells.…”

Section: Discussionmentioning

confidence: 99%

PLA1A Participates in the Antiviral Innate Immune Response by Facilitating the Recruitment of TANK-Binding Kinase 1 to Mitochondria

et al. 2018

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As a key molecule in the antiviral innate immune response, the activation of TANK-binding kinase 1 (TBK1) is under tight regulation. In this report, we identified phosphatidylserine-specific phospholipase PLA1A as a host factor that modulates the TBK1 activation. Knockdown of PLA1A expression suppressed the innate immune signaling induced by RNA viruses, while PLA1A overexpression enhanced the signaling. PLA1A functioned at the TBK1 level of the signaling pathway, as PLA1A silencing blocked TBK1, but not interferon regulatory factor 3 (IRF3) induced interferon-β (IFN-β) promoter activity. The phosphorylation and kinase activity of TBK1 was reduced in PLA1A knockdown cells. Mechanistically, PLA1A was required in TBK1-mitochondrial antiviral signaling protein (MAVS) interactions but not the interactions of TBK1 with other adaptor proteins. Furthermore, PLA1A knockdown reduced the recruitment of TBK1 and IRF3 to mitochondria, concomitant with altered mitochondria morphology.

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“…ROS can induce aggregation of MAVS on mitochondrial outer membrane to initiate IFN response. Cells with reduced ETC activity are impaired with production of IFNs and proinflammatory cytokines during viral infection . In contrast, increased ROS production counteracts HCV replication .…”

Section: The Mutual Interactions Between Hepatitis Viruses and Mitochmentioning

confidence: 99%

Mitochondria in the biology, pathogenesis, and treatment of hepatitis virus infections

Zhang

et al. 2019

Reviews in Medical Virology

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Summary Hepatitis virus infections affect a large proportion of the global population. The host responds rapidly to viral infection by orchestrating a variety of cellular machineries, in particular, the mitochondrial compartment. Mitochondria actively regulate viral infections through modulation of the cellular innate immunity and reprogramming of metabolism. In turn, hepatitis viruses are able to modulate the morphodynamics and functions of mitochondria, but the mode of actions are distinct with respect to different types of hepatitis viruses. The resulting mutual interactions between viruses and mitochondria partially explain the clinical presentation of viral hepatitis, influence the response to antiviral treatment, and offer rational avenues for novel therapy. In this review, we aim to consider in depth the multifaceted interactions of mitochondria with hepatitis virus infections and emphasize the implications for understanding pathogenesis and advancing therapeutic development.

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RLR-mediated antiviral innate immunity requires oxidative phosphorylation activity

Cited by 48 publications

References 42 publications

Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages

Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages

PLA1A Participates in the Antiviral Innate Immune Response by Facilitating the Recruitment of TANK-Binding Kinase 1 to Mitochondria

Mitochondria in the biology, pathogenesis, and treatment of hepatitis virus infections

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