page_title: Toll-like receptor
section_title: TLRs in Drosophila immunity
hierarchical_section_title: Toll-like receptor / Extended family / TLRs in Drosophila immunity
caption_attribution_description: English: A summary diagram of Toll signalling as found in Drosophila melanogaster. The following resources were used in generating this summary (PMID included): 17201680, 31018123, 21209287, 27776480
context_page_description: Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13, though the last three are not found in humans.
  TLR's received their name from their similarity to the protein coded by the toll gene identified in Drosophila in 1985 by Christiane Nüsslein-Volhard and Eric Wieschaus.
context_section_description: The involvement of Toll signalling in immunity was first demonstrated in the fruit fly, Drosophila melanogaster. Fruit flies have only innate immune responses. The fly response to fungal or bacterial infection occurs through two distinct signalling cascades, one of which is the toll pathway and the other is the immune deficiency (IMD) pathway. The toll pathway is similar to mammalian TLR signalling, but unlike mammalian TLRs, toll is not activated directly by pathogen-associated molecular patterns (PAMPs). Its receptor ectodomain recognizes the cleaved form of the cytokine Spätzle, which is secreted in the haemolymph as an inactive dimeric precursor. The Toll receptor shares the cytoplasmatic TIR domain with mammalian TLRs, but the ectodomain and intracytoplasmatic tail are different. This difference might reflect a function of these receptors as cytokine receptors rather than PRRs. 
  The Toll pathway is activated by different stimuli, such as Gram positive bacteria, fungi and virulence factors. First, the Spätzle processing enzyme (SPE) is activated in response to infection and cleaves Spätzle (spz). Cleaved Spätzle then binds to the Toll receptor and crosslinks its ectodomains. This triggers conformational changes in the receptor resulting in signalling through Toll. From this point forward, the signalling cascade is very similar to mammalian signalling through TLRs. The Toll-induced signalling complex (TICS) is composed of MyD88, Tube, and Pelle (the orthologue of mammalian IRAK). Signal from TICS is then transduced to Cactus (homologue of mammalian IκB), phosphorylated Cactus is polyubiquitylated and degraded, allowing nuclear translocation of DIF (dorsal-related immunity factor; a homologue of mammalian NF-κB) and induction of transcription of genes for antimicrobial peptides (AMPs) such as Drosomycin.
  Drosophilia have a total of 9 toll family and 6 spz family genes that interact with each other to differing degrees.
caption: The Toll immunity pathway as found in the fruit fly[12][13][14][15]
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