Drosophila Toll-9 is induced by aging and neurodegeneration to modulate stress signaling and its deficiency exacerbates tau-mediated neurodegeneration

Sakakibara, Yasufumi; Yamashiro, Risa; Chikamatsu, Sachie; Hirota, Yu; Tsubokawa, Yoko; Nishijima, Risa; Takei, Kimi; Sekiya, Michiko; Iijima, Koichi

doi:10.1016/j.isci.2023.105968

Cited by 5 publications

(2 citation statements)

References 111 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, recent studies highlight significant roles for Toll-9 in cell competition, aging, and neurodegeneration. Specifically, Toll-9 mediates apoptosis in unhealthy cells and promotes proliferation in fit cells (Alpar, Bergantiños, and Johnston 2018; Shields et al 2022; Sakakibara et al 2023). Despite these advances, Toll-9’s role in viral infections, its specific activator ligand, and the mechanistic details of its signaling cascade remain elusive and warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, the activation of Toll-9 signaling has been shown to induce apoptosis during cell competition in developing tissues, thereby eliminating unfit cells and promoting proliferation in surviving cells (Meyer et al 2014; Shields et al 2022). Furthermore, Toll-9 has been shown to regulate aging and neurodegenerative processes in a Drosophila model of tauopathy (Sakakibara et al 2023).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Drosophila melanogasterToll-9 elicits antiviral immunity againstDrosophilaC virus

Chauhan,

Martinak,

Hollenberg

et al. 2024

Preprint

View full text Add to dashboard Cite

The Toll pathway plays a pivotal role in innate immune responses against pathogens. The evolutionary conserved pathogen recognition receptors (PRRs), including Toll like receptors (TLRs), play a crucial role in recognition of pathogen associated molecular patterns (PAMPs). TheDrosophilagenome encodes nine Toll receptors that are orthologous to mammalian TLRs. While mammalian TLRs directly recognize PAMPs, mostDrosophilaTolls recognize the proteolytically cleaved ligand Spätzle to activate downstream signaling cascades. In this study, we demonstrated that Toll-9 is crucial for antiviral immunity againstDrosophilaC virus (DCV), a natural pathogen ofDrosophila. A transposable element insertion in theToll-9gene renders the flies more susceptible to DCV. The stable expression of Toll-9 in S2 cells confers resistance against DCV infection by upregulation of the RNAi pathway. Toll-9 promotes the dephosphorylation of AKT, resulting in the induction of antiviral RNAi genes to inhibit DCV replication. Toll-9 localizes to the endosome where it binds dsRNA, suggesting its role to detect viral dsRNA. Toll-9 also induces apoptosis during DCV infection, contributing to its antiviral role. Together, this work identifies the role of Toll-9 in antiviral immunity against DCV infection through its ability to bind dsRNA and induce AKT-mediated RNAi antiviral immunity.IMPORTANCEInsects rely on innate immunity and RNA interference (RNAi) to combat viral infections. Our study underscores the pivotal role ofDrosophilaToll-9 in antiviral immunity, aligning with findings inBombyx mori, where Toll-9 activation upregulates the RNAi componentDicer2. We demonstrate thatDrosophilaToll-9 functions as a pattern recognition receptor (PRR) for double-stranded RNA (dsRNA) duringDrosophila Cvirus (DCV) infection, akin to mammalian TLRs. Toll-9 activation leads to the upregulation of key RNAi components,Dicer2andArgonaute2, and dephosphorylation of AKT triggers apoptosis via induction of proapoptotic genesHidandReaper. This study also reveals that Toll-9 localizes in endosomal compartments where it interacts with dsRNA. These insights enhance our understanding ofDrosophilainnate immune mechanisms, reflecting the evolutionary conservation of immune responses across diverse species and providing impetus for further research into the conserved roles of TLRs across the animal kingdom.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Drosophila melanogasterToll-9 elicits antiviral immunity againstDrosophilaC virus

Chauhan,

Martinak,

Hollenberg

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Immunological function of Bombyx Toll9‐2 in the silkworm (Bombyx mori) larval midgut: Activation by Escherichia coli/lipopolysaccharide and regulation of growth

Liu,

Yang,

Liao

et al. 2024

Arch Insect Biochem Physiol

View full text Add to dashboard Cite

Toll receptors are important regulators of insects' innate immune system which, upon binding of pathogen molecules, activate a conserved signal transduction cascade known as the Toll pathway. RNA interference (RNAi) is a powerful tool to study the function of genes via reverse genetics. However, due to the reported refractory of RNAi efficiency in lepidopteran insects, successful reports of silencing of Toll receptors in the silkworm Bombyx mori have not been reported yet. In this study, a Toll receptor of the silkworm Bombyx Toll9‐2 (BmToll9‐2) was cloned and its expression and function were analyzed. The results showed that BmToll9‐2 contains an ectodomain (ECD) with a signal peptide and nine leucine‐rich repeats, a transmembrane helix, and a cytoplasmic region with a Toll/interleukin‐1 domain. Phylogenetic analysis indicates that BmToll9‐2 clusters with other insect Toll9 receptors and mammalian Toll‐like receptor 4. Oral infection of exogenous pathogens showed that the Gram‐negative bacterium Escherichia coli and its main cell wall component lipopolysaccharide (LPS), as well as the Gram‐positive bacterium Staphylococcus aureus and its main cell wall component peptidoglycan, significantly induce BmToll9‐2 expression in vivo. LPS also induced the expression of BmToll9‐2 in BmN4 cells in vitro. These observations indicate its role as a sensor in the innate immunity to exogenous pathogens and as a pathogen‐associated receptor that is responsive to LPS. RNAi of BmToll9‐2 was effective in the midgut and epidermis. RNAi‐mediated knock‐down of BmToll9‐2 reduced the weight and growth of the silkworm. Bacterial challenge following RNAi upregulated the expression of BmToll9‐2 and rescued the weight differences of the silkworm, which may be related to its participation in the immune response and the regulation of the microbiota in the midgut lumen of the silkworm larvae.

show abstract

Toll-9 prevents the proliferation of injected oncogenic cells in adult flies

Ji,

Hoffmann

2024

Journal of Genetics and Genomics

View full text Add to dashboard Cite

Drosophila Toll-9 is induced by aging and neurodegeneration to modulate stress signaling and its deficiency exacerbates tau-mediated neurodegeneration

Cited by 5 publications

References 111 publications

Drosophila melanogasterToll-9 elicits antiviral immunity againstDrosophilaC virus

Drosophila melanogasterToll-9 elicits antiviral immunity againstDrosophilaC virus

Immunological function of Bombyx Toll9‐2 in the silkworm (Bombyx mori) larval midgut: Activation by Escherichia coli/lipopolysaccharide and regulation of growth

Toll-9 prevents the proliferation of injected oncogenic cells in adult flies

Contact Info

Product

Resources

About