Toll-8/Tollo Negatively Regulates Antimicrobial Response in the Drosophila Respiratory Epithelium

Akhouayri, Idir; Turc, Claire; Royet, Julien; Charroux, Bernard

doi:10.1371/journal.ppat.1002319

Cited by 83 publications

(62 citation statements)

References 64 publications

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“…However, the limited duration of axon protection afforded by DLK ablation argues against its centrality in an axon degeneration pathway. Indeed, we and others have identified additional molecules whose loss or inhibition delays injury-induced axon degeneration (Barrientos et al, 2011;Gerdts et al, 2011;Wakatsuki et al, 2011;Bhattacharya et al, 2012;Babetto et al, 2013).…”

Section: Introductionmentioning

confidence: 77%

“…The TIR adaptor proteins have been well studied as dynamic scaffold molecules promoting the downstream signaling of Toll-like receptors and have important roles in innate immunity (O'Neill and Bowie, 2007). SARM is unique among these proteins in that it has been reported to act as a negative regulator of innate immunity signaling (Carty et al, 2006;Akhouayri et al, 2011). Unlike the other TIR adaptors, SARM is preferentially expressed in the nervous system (Kim et al, 2007) and is linked to neural cell fate specification (Chuang and Bargmann, 2005), dendritic arborization (Chen et al, 2011), and microglial activation (Szretter et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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Sarm1-Mediated Axon Degeneration Requires Both SAM and TIR Interactions

et al. 2013

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Axon degeneration is an evolutionarily conserved pathway that eliminates damaged or unneeded axons. Manipulation of this poorly understood pathway may allow treatment of a wide range of neurological disorders. In an RNAi-based screen performed in cultured mouse DRG neurons, we observed strong suppression of injury-induced axon degeneration upon knockdown of Sarm1 [SARM (sterile ␣-motif-containing and armadillo-motif containing protein)]. We find that a SARM-dependent degeneration program is engaged by disparate neuronal insults: SARM ablation blocks axon degeneration induced by axotomy or vincristine treatment, while SARM acts in parallel with a soma-derived caspase-dependent pathway following trophic withdrawal. SARM is a multidomain protein that associates with neuronal mitochondria. Deletion of the N-terminal mitochondrial localization sequence disrupts SARM mitochondrial localization in neurons but does not alter its ability to promote axon degeneration. In contrast, mutation of either the SAM (sterile ␣ motif) or TIR (Toll-interleukin-1 receptor) domains abolishes the ability of SARM to promote axonal degeneration, while a SARM mutant containing only these domains elicits axon degeneration and nonapoptotic neuronal death even in the absence of injury. Protein-protein interaction studies demonstrate that the SAM domains are necessary and sufficient to mediate SARM-SARM binding. SARM mutants lacking a TIR domain bind full-length SARM and exhibit strong dominant-negative activity. These results indicate that SARM plays an integral role in the dismantling of injured axons and support a model in which SAM-mediated multimerization is necessary for TIR-dependent engagement of a downstream destruction pathway. These findings suggest that inhibitors of SAM and TIR interactions represent therapeutic candidates for blocking pathological axon loss and neuronal cell death.

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Section: Introductionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Sarm1-Mediated Axon Degeneration Requires Both SAM and TIR Interactions

et al. 2013

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“…Although the sizes of the families of Toll receptors in Drosophila and mammals are similar, with about 10 members, phylogenetic analysis has clearly indicated that Toll receptors evolved independently in different animal phyla (48,49). In Drosophila, only Toll itself has so far been shown to participate in the induction of an immune response in flies, although Toll-8 acts as a negative regulator of antimicrobial defenses in the respiratory tract (50)(51)(52)(53). Drosophila Toll receptors are highly expressed during embryogenesis, pointing to developmental functions (49,54).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Contribution of Hemocytes and Autophagy to Drosophila Antiviral Immunity

Lamiable

Arnold

Faria

et al. 2016

J Virol

112

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Antiviral immunity in the model organism Drosophila melanogaster involves the broadly active intrinsic mechanism of RNA interference (RNAi) and virus-specific inducible responses. Here, using a panel of six viruses, we investigated the role of hemocytes and autophagy in the control of viral infections. Injection of latex beads to saturate phagocytosis, or genetic depletion of hemocytes, resulted in decreased survival and increased viral titers following infection with Cricket paralysis virus (CrPV), Flock House virus (FHV), and vesicular stomatitis virus (VSV) but had no impact on Drosophila C virus (DCV), Sindbis virus (SINV), and Invertebrate iridescent virus 6 (IIV6) infection. In the cases of CrPV and FHV, apoptosis was induced in infected cells, which were phagocytosed by hemocytes. In contrast, VSV did not trigger any significant apoptosis but we confirmed that the autophagy gene Atg7 was required for full virus resistance, suggesting that hemocytes use autophagy to recognize the virus. However, this recognition does not depend on the Toll-7 receptor. Autophagy had no impact on DCV, CrPV, SINV, or IIV6 infection and was required for replication of the sixth virus, FHV. Even in the case of VSV, the increases in titers were modest in Atg7 mutant flies, suggesting that autophagy does not play a major role in antiviral immunity in Drosophila. Altogether, our results indicate that, while autophagy plays a minor role, phagocytosis contributes to virus-specific immune responses in insects. IMPORTANCEPhagocytosis and autophagy are two cellular processes that involve lysosomal degradation and participate in Drosophila immunity. Using a panel of RNA and DNA viruses, we have addressed the contribution of phagocytosis and autophagy in the control of viral infections in this model organism. We show that, while autophagy plays a minor role, phagocytosis contributes to virusspecific immune responses in Drosophila. This work brings to the front a novel facet of antiviral host defense in insects, which may have relevance in the control of virus transmission by vector insects or in the resistance of beneficial insects to viral pathogens.

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“…In humans, Toll-like receptor 4 (TLR4) can bind lipopolysaccharide on the surface of bacteria (36), whereas TLR3 recognizes double-stranded RNA, leading to the activation of the NF-B pathway (37). Drosophila Toll7 recognizes viruses and activates antiviral autophagy (38), Drosophila Toll8 negatively regulates the antimicrobial response (39), and Drosophila Toll1 regulates the systemic immune response (40). This study showed that Toll1, Toll4, Toll6, and Toll7 play important roles in antiviral immunity in shrimp.…”

Section: Discussionmentioning

confidence: 99%

Two White Spot Syndrome Virus MicroRNAs Target the Dorsal Gene To Promote Virus Infection in Marsupenaeus japonicus Shrimp

Ren

Huang

Cui

et al. 2017

J Virol

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In eukaryotes, microRNAs (miRNAs) serve as regulators of many biological processes, including virus infection. An miRNA can generally target diverse genes during virus-host interactions. However, the regulation of gene expression by multiple miRNAs has not yet been extensively explored during virus infection. This study found that the Spaztle (Spz)-Toll-Dorsal-antilipopolysaccharide factor (ALF) signaling pathway plays a very important role in antiviral immunity against invasion of white spot syndrome virus (WSSV) in shrimp (Marsupenaeus japonicus). Dorsal, the central gene in the Toll pathway, was targeted by two viral miRNAs (WSSV-miR-N13 and WSSV-miR-N23) during WSSV infection. The regulation of Dorsal expression by viral miRNAs suppressed the Spz-Toll-Dorsal-ALF signaling pathway in shrimp in vivo, leading to virus infection. Our study contributes novel insights into the viral miRNAmediated Toll signaling pathway during the virus-host interaction.IMPORTANCE An miRNA can target diverse genes during virus-host interactions. However, the regulation of gene expression by multiple miRNAs during virus infection has not yet been extensively explored. The results of this study indicated that the shrimp Dorsal gene, the central gene in the Toll pathway, was targeted by two viral miRNAs during infection with white spot syndrome virus. Regulation of Dorsal expression by viral miRNAs suppressed the Spz-Toll-Dorsal-ALF signaling pathway in shrimp in vivo, leading to virus infection. Our study provides new insight into the viral miRNA-mediated Toll signaling pathway in virus-host interactions.

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Toll-8/Tollo Negatively Regulates Antimicrobial Response in the Drosophila Respiratory Epithelium

Cited by 83 publications

References 64 publications

Sarm1-Mediated Axon Degeneration Requires Both SAM and TIR Interactions

Sarm1-Mediated Axon Degeneration Requires Both SAM and TIR Interactions

Analysis of the Contribution of Hemocytes and Autophagy to Drosophila Antiviral Immunity

Two White Spot Syndrome Virus MicroRNAs Target the Dorsal Gene To Promote Virus Infection in Marsupenaeus japonicus Shrimp

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