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Bacterial and fungal pattern recognition receptors in homologous innate signaling pathways of insects and mammals.

Stokes BA, Yadav S, Shokal U, Smith LC, Eleftherianos I - Front Microbiol (2015)

Bottom Line: Insect and mammalian innate immune receptors include molecules that recognize conserved microbial molecular patterns.Innate immune recognition leads to the recruitment of adaptor molecules forming multi-protein complexes that include kinases, transcription factors, and other regulatory molecules.Innate immune signaling cascades induce the expression of genes encoding antimicrobial peptides and other key factors that mount and regulate the immune response against microbial challenge.

View Article: PubMed Central - PubMed

Affiliation: Insect Infection and Immunity Laboratory, Department of Biological Sciences, The George Washington University Washington, DC, USA.

ABSTRACT
In response to bacterial and fungal infections in insects and mammals, distinct families of innate immune pattern recognition receptors (PRRs) initiate highly complex intracellular signaling cascades. Those cascades induce a variety of immune functions that restrain the spread of microbes in the host. Insect and mammalian innate immune receptors include molecules that recognize conserved microbial molecular patterns. Innate immune recognition leads to the recruitment of adaptor molecules forming multi-protein complexes that include kinases, transcription factors, and other regulatory molecules. Innate immune signaling cascades induce the expression of genes encoding antimicrobial peptides and other key factors that mount and regulate the immune response against microbial challenge. In this review, we summarize our current understanding of the bacterial and fungal PRRs for homologous innate signaling pathways of insects and mammals in an effort to provide a framework for future studies.

No MeSH data available.


Related in: MedlinePlus

The Toll pathway in the fruit fly and the Toll-like receptor (TLR) 4 pathway in the mouse. (A) The Toll pathway in Drosophila melanogaster mainly detects fungi and Gram-positive bacteria. The Toll receptor is triggered upon binding by the cleaved form of the cytokine Spaetzle, which is processed by Spaetzle-processing enzyme (SPE) and other serine proteases that are regulated by the pathogen recognition peptidoglycan recognition proteins (PGRP) PGRP-SA, PGRP-SD, GNBP1, and GNBP3. Serine protease Persephone (Psh) is activated by virulence factors secreted by entomopathogenic fungi and is regulated by Necrotic, a Psh inhibitor. Toll receptor activation results in the recruitment of adaptor proteins in the cytoplasm including myeloid differentiation primary response 88 (dMyD88), Tube, and Pelle, which promotes signaling to Cactus and its ankyrin-repeat domains. Cactus is normally bound to the Nuclear Factor kappa B (NF-κB) transcription factors Dorsal-related Immunity Factor (DIF) and Dorsal, but upon activation of the signaling pathway, it is phosophorylated, dissociated from DIF or Dorsal and degraded. These signaling events result in the nuclear translocation of DIF or Dorsal that induce the transcriptional upregulation of antimicrobial peptide (AMP) genes, such as Drosomycin. (B) TLR4 receptor in Mus musculus functions together with Lymphocyte Antigen 96 (MD2) and Cluster of Differentiation 14 (CD14) to detect lipopolysaccharides (LPS) from Gram-negative bacteria. MyD88 is recruited with Interleukin-1 receptor-associated kinases 1 and 4 (IRAK1, IRAK4), receptor-interacting protein 1 (RIP1) and Tumor Necrosis Factor (TNF) receptor associated factor 6 (TRAF6). The latter ubiquitinates itself to recruit Transforming Growth Factor beta (TGF-β) activated kinase 1 (TAK1) and TAK1-associated binding proteins 1 and 2 (TAB1 and TAB2), which result in the activation of the IκB kinase (IKK) complex that phosphorylates the Inhibitor of NF-κB (IκB). This leads to the release of NF-κB that translocates to the nucleus and initiates the transcriptional induction of inflammatory and immune response related genes.
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Figure 1: The Toll pathway in the fruit fly and the Toll-like receptor (TLR) 4 pathway in the mouse. (A) The Toll pathway in Drosophila melanogaster mainly detects fungi and Gram-positive bacteria. The Toll receptor is triggered upon binding by the cleaved form of the cytokine Spaetzle, which is processed by Spaetzle-processing enzyme (SPE) and other serine proteases that are regulated by the pathogen recognition peptidoglycan recognition proteins (PGRP) PGRP-SA, PGRP-SD, GNBP1, and GNBP3. Serine protease Persephone (Psh) is activated by virulence factors secreted by entomopathogenic fungi and is regulated by Necrotic, a Psh inhibitor. Toll receptor activation results in the recruitment of adaptor proteins in the cytoplasm including myeloid differentiation primary response 88 (dMyD88), Tube, and Pelle, which promotes signaling to Cactus and its ankyrin-repeat domains. Cactus is normally bound to the Nuclear Factor kappa B (NF-κB) transcription factors Dorsal-related Immunity Factor (DIF) and Dorsal, but upon activation of the signaling pathway, it is phosophorylated, dissociated from DIF or Dorsal and degraded. These signaling events result in the nuclear translocation of DIF or Dorsal that induce the transcriptional upregulation of antimicrobial peptide (AMP) genes, such as Drosomycin. (B) TLR4 receptor in Mus musculus functions together with Lymphocyte Antigen 96 (MD2) and Cluster of Differentiation 14 (CD14) to detect lipopolysaccharides (LPS) from Gram-negative bacteria. MyD88 is recruited with Interleukin-1 receptor-associated kinases 1 and 4 (IRAK1, IRAK4), receptor-interacting protein 1 (RIP1) and Tumor Necrosis Factor (TNF) receptor associated factor 6 (TRAF6). The latter ubiquitinates itself to recruit Transforming Growth Factor beta (TGF-β) activated kinase 1 (TAK1) and TAK1-associated binding proteins 1 and 2 (TAB1 and TAB2), which result in the activation of the IκB kinase (IKK) complex that phosphorylates the Inhibitor of NF-κB (IκB). This leads to the release of NF-κB that translocates to the nucleus and initiates the transcriptional induction of inflammatory and immune response related genes.

Mentions: The Toll pathway in insects is mainly responsible for the recognition of fungi and Gram-positive bacteria and the induction of certain AMPs that are secreted into the insect hemolymph (Lemaitre and Hoffmann, 2007; Tsakas and Marmaras, 2010). Toll is a transmembrane protein composed of extracellular leucine-rich repeat modules and a cytoplasmic Toll-Interleukin-1-receptor (TIR) domain that initiates signaling. It was originally characterized based on its function in the dorsal-ventral pattern formation in the Drosophila embryo, but it was subsequently shown that Toll is also required for innate immune signaling (Hashimoto et al., 1988; Lemaitre et al., 1996). Drosophila Toll does not interact directly with microbial structures, but instead receives signals from recognition proteins in the hemolymph that converge a signal of microbial presence on Spaetzle, which is the Toll ligand (Weber et al., 2003). Upon Gram-positive bacterial infection, Toll relies on the function of three pathogen recognition proteins that detect the bacteria and trigger a serine protease cascade that activates the Spaetzle-processing enzyme (SPE) that cleaves Spaetzle into the fragment that binds Toll. This induces Toll to initiate intracellular signaling that recruits adaptor proteins, myeloid differentiation primary response 88 (MyD88), Tube, and Pelle [an interleukin-1 receptor-associated kinases (IRAK) ortholog], and signals through a poorly defined pathway to Cactus [inhibitor of kappa B (IκB) homolog], which is bound to the Rel homology domains of the transcription factors Dorsal-related Immunity Factor (DIF), Nuclear Factor κB (NF-κB) homolog, and Dorsal through its six ankyrin-repeats. Cactus phosphorylation and subsequent ubiquitination and degradation by the proteasome leads to the release of DIF that moves to the nucleus and induces the transcriptional activation of the AMP genes (Valanne et al., 2011; Lindsay and Wasserman, 2014). Without the initial signaling from the extracellular protease cascade and activation of Toll, the intracellular reactions cannot induce production of antibacterial proteins, rendering the insect susceptible to infection (Figure 1A).


Bacterial and fungal pattern recognition receptors in homologous innate signaling pathways of insects and mammals.

Stokes BA, Yadav S, Shokal U, Smith LC, Eleftherianos I - Front Microbiol (2015)

The Toll pathway in the fruit fly and the Toll-like receptor (TLR) 4 pathway in the mouse. (A) The Toll pathway in Drosophila melanogaster mainly detects fungi and Gram-positive bacteria. The Toll receptor is triggered upon binding by the cleaved form of the cytokine Spaetzle, which is processed by Spaetzle-processing enzyme (SPE) and other serine proteases that are regulated by the pathogen recognition peptidoglycan recognition proteins (PGRP) PGRP-SA, PGRP-SD, GNBP1, and GNBP3. Serine protease Persephone (Psh) is activated by virulence factors secreted by entomopathogenic fungi and is regulated by Necrotic, a Psh inhibitor. Toll receptor activation results in the recruitment of adaptor proteins in the cytoplasm including myeloid differentiation primary response 88 (dMyD88), Tube, and Pelle, which promotes signaling to Cactus and its ankyrin-repeat domains. Cactus is normally bound to the Nuclear Factor kappa B (NF-κB) transcription factors Dorsal-related Immunity Factor (DIF) and Dorsal, but upon activation of the signaling pathway, it is phosophorylated, dissociated from DIF or Dorsal and degraded. These signaling events result in the nuclear translocation of DIF or Dorsal that induce the transcriptional upregulation of antimicrobial peptide (AMP) genes, such as Drosomycin. (B) TLR4 receptor in Mus musculus functions together with Lymphocyte Antigen 96 (MD2) and Cluster of Differentiation 14 (CD14) to detect lipopolysaccharides (LPS) from Gram-negative bacteria. MyD88 is recruited with Interleukin-1 receptor-associated kinases 1 and 4 (IRAK1, IRAK4), receptor-interacting protein 1 (RIP1) and Tumor Necrosis Factor (TNF) receptor associated factor 6 (TRAF6). The latter ubiquitinates itself to recruit Transforming Growth Factor beta (TGF-β) activated kinase 1 (TAK1) and TAK1-associated binding proteins 1 and 2 (TAB1 and TAB2), which result in the activation of the IκB kinase (IKK) complex that phosphorylates the Inhibitor of NF-κB (IκB). This leads to the release of NF-κB that translocates to the nucleus and initiates the transcriptional induction of inflammatory and immune response related genes.
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Related In: Results  -  Collection

License
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Figure 1: The Toll pathway in the fruit fly and the Toll-like receptor (TLR) 4 pathway in the mouse. (A) The Toll pathway in Drosophila melanogaster mainly detects fungi and Gram-positive bacteria. The Toll receptor is triggered upon binding by the cleaved form of the cytokine Spaetzle, which is processed by Spaetzle-processing enzyme (SPE) and other serine proteases that are regulated by the pathogen recognition peptidoglycan recognition proteins (PGRP) PGRP-SA, PGRP-SD, GNBP1, and GNBP3. Serine protease Persephone (Psh) is activated by virulence factors secreted by entomopathogenic fungi and is regulated by Necrotic, a Psh inhibitor. Toll receptor activation results in the recruitment of adaptor proteins in the cytoplasm including myeloid differentiation primary response 88 (dMyD88), Tube, and Pelle, which promotes signaling to Cactus and its ankyrin-repeat domains. Cactus is normally bound to the Nuclear Factor kappa B (NF-κB) transcription factors Dorsal-related Immunity Factor (DIF) and Dorsal, but upon activation of the signaling pathway, it is phosophorylated, dissociated from DIF or Dorsal and degraded. These signaling events result in the nuclear translocation of DIF or Dorsal that induce the transcriptional upregulation of antimicrobial peptide (AMP) genes, such as Drosomycin. (B) TLR4 receptor in Mus musculus functions together with Lymphocyte Antigen 96 (MD2) and Cluster of Differentiation 14 (CD14) to detect lipopolysaccharides (LPS) from Gram-negative bacteria. MyD88 is recruited with Interleukin-1 receptor-associated kinases 1 and 4 (IRAK1, IRAK4), receptor-interacting protein 1 (RIP1) and Tumor Necrosis Factor (TNF) receptor associated factor 6 (TRAF6). The latter ubiquitinates itself to recruit Transforming Growth Factor beta (TGF-β) activated kinase 1 (TAK1) and TAK1-associated binding proteins 1 and 2 (TAB1 and TAB2), which result in the activation of the IκB kinase (IKK) complex that phosphorylates the Inhibitor of NF-κB (IκB). This leads to the release of NF-κB that translocates to the nucleus and initiates the transcriptional induction of inflammatory and immune response related genes.
Mentions: The Toll pathway in insects is mainly responsible for the recognition of fungi and Gram-positive bacteria and the induction of certain AMPs that are secreted into the insect hemolymph (Lemaitre and Hoffmann, 2007; Tsakas and Marmaras, 2010). Toll is a transmembrane protein composed of extracellular leucine-rich repeat modules and a cytoplasmic Toll-Interleukin-1-receptor (TIR) domain that initiates signaling. It was originally characterized based on its function in the dorsal-ventral pattern formation in the Drosophila embryo, but it was subsequently shown that Toll is also required for innate immune signaling (Hashimoto et al., 1988; Lemaitre et al., 1996). Drosophila Toll does not interact directly with microbial structures, but instead receives signals from recognition proteins in the hemolymph that converge a signal of microbial presence on Spaetzle, which is the Toll ligand (Weber et al., 2003). Upon Gram-positive bacterial infection, Toll relies on the function of three pathogen recognition proteins that detect the bacteria and trigger a serine protease cascade that activates the Spaetzle-processing enzyme (SPE) that cleaves Spaetzle into the fragment that binds Toll. This induces Toll to initiate intracellular signaling that recruits adaptor proteins, myeloid differentiation primary response 88 (MyD88), Tube, and Pelle [an interleukin-1 receptor-associated kinases (IRAK) ortholog], and signals through a poorly defined pathway to Cactus [inhibitor of kappa B (IκB) homolog], which is bound to the Rel homology domains of the transcription factors Dorsal-related Immunity Factor (DIF), Nuclear Factor κB (NF-κB) homolog, and Dorsal through its six ankyrin-repeats. Cactus phosphorylation and subsequent ubiquitination and degradation by the proteasome leads to the release of DIF that moves to the nucleus and induces the transcriptional activation of the AMP genes (Valanne et al., 2011; Lindsay and Wasserman, 2014). Without the initial signaling from the extracellular protease cascade and activation of Toll, the intracellular reactions cannot induce production of antibacterial proteins, rendering the insect susceptible to infection (Figure 1A).

Bottom Line: Insect and mammalian innate immune receptors include molecules that recognize conserved microbial molecular patterns.Innate immune recognition leads to the recruitment of adaptor molecules forming multi-protein complexes that include kinases, transcription factors, and other regulatory molecules.Innate immune signaling cascades induce the expression of genes encoding antimicrobial peptides and other key factors that mount and regulate the immune response against microbial challenge.

View Article: PubMed Central - PubMed

Affiliation: Insect Infection and Immunity Laboratory, Department of Biological Sciences, The George Washington University Washington, DC, USA.

ABSTRACT
In response to bacterial and fungal infections in insects and mammals, distinct families of innate immune pattern recognition receptors (PRRs) initiate highly complex intracellular signaling cascades. Those cascades induce a variety of immune functions that restrain the spread of microbes in the host. Insect and mammalian innate immune receptors include molecules that recognize conserved microbial molecular patterns. Innate immune recognition leads to the recruitment of adaptor molecules forming multi-protein complexes that include kinases, transcription factors, and other regulatory molecules. Innate immune signaling cascades induce the expression of genes encoding antimicrobial peptides and other key factors that mount and regulate the immune response against microbial challenge. In this review, we summarize our current understanding of the bacterial and fungal PRRs for homologous innate signaling pathways of insects and mammals in an effort to provide a framework for future studies.

No MeSH data available.


Related in: MedlinePlus