RNase L Activates the NLRP3 Inflammasome during Viral Infections

Chakrabarti, Arindam; Banerjee, Shuvomoy; Franchi, Luigi; Loo, Yueh–Ming; Gale, Michael; Núñez, Gabriel; Silverman, Robert H.

doi:10.1016/j.chom.2015.02.010

Cited by 128 publications

(139 citation statements)

References 61 publications

(95 reference statements)

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“…This hypothesis is in agreement with recent published results showing that cellular factors that restrict L1 retrotransposition are also involved in the regulation of exogenous viruses (TREX1, APOBEC3 proteins, SAMHD1, MOV10, RNase L and ZAP) (32,61–63), thus indicating a sort of selection during the evolution of some host proteins to defend cells from endogenous and exogenous parasites. To investigate whether ADAR1 affects L1 activity, we employed two distinct and well-established retrotransposition assay systems (33,34,36).…”

Section: Discussionsupporting

confidence: 93%

ADAR1 restricts LINE-1 retrotransposition

et al. 2016

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Adenosine deaminases acting on RNA (ADARs) are involved in RNA editing that converts adenosines to inosines in double-stranded RNAs. ADAR1 was demonstrated to be functional on different viruses exerting either antiviral or proviral effects. Concerning HIV-1, several studies showed that ADAR1 favors viral replication. The aim of this study was to investigate the composition of the ADAR1 ribonucleoprotein complex during HIV-1 expression. By using a dual-tag affinity purification procedure in cells expressing HIV-1 followed by mass spectrometry analysis, we identified 14 non-ribosomal ADAR1-interacting proteins, most of which are novel. A significant fraction of these proteins were previously demonstrated to be associated to the Long INterspersed Element 1 (LINE1 or L1) ribonucleoparticles and to regulate the life cycle of L1 retrotransposons that continuously re-enter host-genome.Hence, we investigated the function of ADAR1 in the regulation of L1 activity.By using different cell-culture based retrotransposition assays in HeLa cells, we demonstrated a novel function of ADAR1 as suppressor of L1 retrotransposition. Apparently, this inhibitory mechanism does not occur through ADAR1 editing activity. Furthermore, we showed that ADAR1 binds the basal L1 RNP complex. Overall, these data support the role of ADAR1 as regulator of L1 life cycle.

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Section: Discussionsupporting

confidence: 93%

ADAR1 restricts LINE-1 retrotransposition

et al. 2016

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“…The importance of IAV M2 ion channel protein, RIG-I, type I IFN signaling, RIPK3 and RNaseL in mediating inflammasome activation during IAV infection have been demonstrated (18, 19, 34, 36). Our data demonstrating an IAV-specific role for IFNAR–ZBP1 axis in the regulation of NLRP3 inflammasome activation will help to reconcile these findings.…”

Section: Discussionmentioning

confidence: 99%

ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways

et al. 2016

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The interferon-inducible protein Z-DNA binding protein 1 (ZBP1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1) was identified as a dsDNA sensor, which instigates innate immune responses. However, this classification has been disputed and whether ZBP1 functions as a pathogen sensor during an infection has remained unknown. Herein, we demonstrated ZBP1-mediated sensing of the influenza A virus (IAV) proteins NP and PB1, triggering cell death and inflammatory responses via the RIPK1–RIPK3–Caspase-8 axis. ZBP1 regulates NLRP3 inflammasome activation as well as induction of apoptosis, necroptosis and pyroptosis in IAV-infected cells. Importantly, ZBP1 deficiency protected mice from mortality during IAV infection owing to reduced inflammatory responses and epithelial damage. Overall, these findings indicate that ZBP1 is an innate immune sensor of IAV and highlight its importance in the pathogenesis of IAV infection.

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“…Our data also suggest that MAVS itself may also participate in IFN-I-independent control of EBOV infection in tissues. Indeed, MAVS has IFN-I-independent roles in antiviral responses (Olagnier et al, 2014) including ISG expression (Dixit et al, 2010), inflammasome activation (Chakrabarti et al, 2015; Subramanian et al, 2013) and induction of apoptosis (Kumar et al, 2015). In the context of macrophages, MAVS signaling may also participate in cell-to-cell communication through the induction of proinflammatory mediators and promotion of cell-mediated immune responses (Lazear et al, 2013; Suthar et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection

et al. 2017

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SUMMARY The unprecedented 2013–16 outbreak of Ebola virus (EBOV) resulted in over 11,300 human deaths. Host resistance to RNA viruses requires RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling (MAVS), but the role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here, we apply a systems approach to MAVS−/− mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through expression of IFNα, regulation of inflammatory responses in the spleen, and prevention of cell death in the liver, with macrophages implicated as a major cell-type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional MAVS deletion in LysM+ myeloid cells. These findings reveal tissue-specific MAVS-dependent transcriptional pathways associated with resistance to EBOV, and demonstrate that EBOV adaptation to cause disease in mice involves changes in two distinct events, RLR-MAVS antagonism and suppression of RLR-independent IFN-I responses.

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RNase L Activates the NLRP3 Inflammasome during Viral Infections

Cited by 128 publications

References 61 publications

ADAR1 restricts LINE-1 retrotransposition

ADAR1 restricts LINE-1 retrotransposition

ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways

A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection

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