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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 Imd pathway in the fruit fly and the TNF pathway in the mouse. (A) The D. melanogaster Imd signaling pathway is activated upon direct binding between PGRP-LC and meso-diaminopimelic acid (DAP)-type PG of Gram-negative bacteria and certain Gram-positive bacilli. The intracellular adaptor protein Immune deficiency (Imd) interacts with the Drosophila Fas-associated death domain (dFADD) and the Death related ced-3/Nedd2-like caspase (DREDD) that cleaves Imd, which is then activated by K63-ubiquitination. This leads to the activation of the TAK1 and TAB2 complex that in turn activates the IKK signalosome, which is composed of Immune Response Deficient 5 (IRD5) and Kenny (Key). Relish is subsequently cleaved by DREDD. As a result, the Rel DNA-binding domain is released from the C-terminal ankyrin-repeat/IκB-like domain, and translocates to the nucleus to induce transcription of antimicrobial peptide (AMP) genes, such as Diptericin. (B) In Mus musculus, TNF trimers bind and activate the transmembrane receptors R1 and R2 (TNFR1 and TNFR2) that recruit Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD), receptor-interacting protein 1 (RIP1) and TNF receptor-associated factor 2 (TRAF2). The latter employs the Transforming Growth Factor beta (TGF-β) activated kinase 1 (TAK1) (whose activity is directly regulated by K63-linked polyubiquitination) and TAB1 and TAB2 complex to phosphorylate and activate the IKK signalosome, which phosphorylates IκB that dissociates from NF-κB. NF-κB translocates to the nucleus to induce expression of several genes that participate in inflammation and immunity.
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Figure 2: The Imd pathway in the fruit fly and the TNF pathway in the mouse. (A) The D. melanogaster Imd signaling pathway is activated upon direct binding between PGRP-LC and meso-diaminopimelic acid (DAP)-type PG of Gram-negative bacteria and certain Gram-positive bacilli. The intracellular adaptor protein Immune deficiency (Imd) interacts with the Drosophila Fas-associated death domain (dFADD) and the Death related ced-3/Nedd2-like caspase (DREDD) that cleaves Imd, which is then activated by K63-ubiquitination. This leads to the activation of the TAK1 and TAB2 complex that in turn activates the IKK signalosome, which is composed of Immune Response Deficient 5 (IRD5) and Kenny (Key). Relish is subsequently cleaved by DREDD. As a result, the Rel DNA-binding domain is released from the C-terminal ankyrin-repeat/IκB-like domain, and translocates to the nucleus to induce transcription of antimicrobial peptide (AMP) genes, such as Diptericin. (B) In Mus musculus, TNF trimers bind and activate the transmembrane receptors R1 and R2 (TNFR1 and TNFR2) that recruit Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD), receptor-interacting protein 1 (RIP1) and TNF receptor-associated factor 2 (TRAF2). The latter employs the Transforming Growth Factor beta (TGF-β) activated kinase 1 (TAK1) (whose activity is directly regulated by K63-linked polyubiquitination) and TAB1 and TAB2 complex to phosphorylate and activate the IKK signalosome, which phosphorylates IκB that dissociates from NF-κB. NF-κB translocates to the nucleus to induce expression of several genes that participate in inflammation and immunity.

Mentions: The Imd effect was identified by the severely impacted immune phenotypes produced by Drosophila mutants in the intracellular adaptor protein Imd, which interacts with the Drosophila Fas-associated death domain ortholog (dFADD) that binds to Death related ced-3/Nedd2-like caspase (DREDD). Imd is cleaved by DREDD and is subsequently activated by K63-ubiquitination (Paquette et al., 2010). Fly mutants for Imd are characterized by the lack of AMP production and an increased susceptibility to Gram-negative bacteria (Lemaitre et al., 1995). Similar to the mechanistic structure of the Toll pathway, Imd integrates the activation signal through intracellular adaptor proteins that converge on inducing the nuclear translocation of Relish, another homolog of NF-κB. Relish is activated by Immune Response Deficient 5 (IRD5; IKKβ homolog) and Kenny (Key; IKKγ homolog) which form the fly IKK signalosome that is phosphorylated and activated by the TAK1/TAB2 complex (Kleino and Silverman, 2014). The caspase DREDD cleaves Relish, removing the C-terminal inhibitor ankyrin-repeat/IκB-like domain, which remains in the cytoplasm, which allows the Rel DNA-binding domain (Rel68) to translocate to the nucleus where it induces the transcription of target genes. Target genes in the Imd pathway code for AMPs such as Diptericin and Cecropin, which act against Gram-negative bacteria (Figure 2A). The insect Imd pathway is homologous to the mammalian TNF signaling pathway based on the intracellular mechanisms, although the recognition receptors are different (Lemaitre and Hoffmann, 2007). In mammals, trimeric forms of TNF bind and activate TNF receptor 1 and 2 (TNFR1, TNFR2) cytoplasmic receptors that recruit a cytoplasmic complex composed of tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD), RIP1 and TRAF2 that activates the IKK signalosome via the TAK1/TAB1/TAB2 complex leading to NF-κB translocation and transcriptional induction of genes that modulate inflammation and immune function (Figure 2B). Imd is highly homologous to the mammalian RIP1, which binds to the cytoplasmic domain of the TNFR (Hsu et al., 1996). Both Imd and TNFR signaling induce the recruitment of adaptor proteins through death domain interactions, which results in a phosphorylation cascade to induce NF-κB-mediated transcriptional activation of antibacterial molecules and cytokines (Georgel et al., 2001). Therefore, while the receptor mechanisms are not inherently homologous, they are critically important to the integration of information that is transduced to their homologous intracellular counterparts, which illuminates key parallels between insect and mammalian innate immune systems.


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 Imd pathway in the fruit fly and the TNF pathway in the mouse. (A) The D. melanogaster Imd signaling pathway is activated upon direct binding between PGRP-LC and meso-diaminopimelic acid (DAP)-type PG of Gram-negative bacteria and certain Gram-positive bacilli. The intracellular adaptor protein Immune deficiency (Imd) interacts with the Drosophila Fas-associated death domain (dFADD) and the Death related ced-3/Nedd2-like caspase (DREDD) that cleaves Imd, which is then activated by K63-ubiquitination. This leads to the activation of the TAK1 and TAB2 complex that in turn activates the IKK signalosome, which is composed of Immune Response Deficient 5 (IRD5) and Kenny (Key). Relish is subsequently cleaved by DREDD. As a result, the Rel DNA-binding domain is released from the C-terminal ankyrin-repeat/IκB-like domain, and translocates to the nucleus to induce transcription of antimicrobial peptide (AMP) genes, such as Diptericin. (B) In Mus musculus, TNF trimers bind and activate the transmembrane receptors R1 and R2 (TNFR1 and TNFR2) that recruit Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD), receptor-interacting protein 1 (RIP1) and TNF receptor-associated factor 2 (TRAF2). The latter employs the Transforming Growth Factor beta (TGF-β) activated kinase 1 (TAK1) (whose activity is directly regulated by K63-linked polyubiquitination) and TAB1 and TAB2 complex to phosphorylate and activate the IKK signalosome, which phosphorylates IκB that dissociates from NF-κB. NF-κB translocates to the nucleus to induce expression of several genes that participate in inflammation and immunity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4309185&req=5

Figure 2: The Imd pathway in the fruit fly and the TNF pathway in the mouse. (A) The D. melanogaster Imd signaling pathway is activated upon direct binding between PGRP-LC and meso-diaminopimelic acid (DAP)-type PG of Gram-negative bacteria and certain Gram-positive bacilli. The intracellular adaptor protein Immune deficiency (Imd) interacts with the Drosophila Fas-associated death domain (dFADD) and the Death related ced-3/Nedd2-like caspase (DREDD) that cleaves Imd, which is then activated by K63-ubiquitination. This leads to the activation of the TAK1 and TAB2 complex that in turn activates the IKK signalosome, which is composed of Immune Response Deficient 5 (IRD5) and Kenny (Key). Relish is subsequently cleaved by DREDD. As a result, the Rel DNA-binding domain is released from the C-terminal ankyrin-repeat/IκB-like domain, and translocates to the nucleus to induce transcription of antimicrobial peptide (AMP) genes, such as Diptericin. (B) In Mus musculus, TNF trimers bind and activate the transmembrane receptors R1 and R2 (TNFR1 and TNFR2) that recruit Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD), receptor-interacting protein 1 (RIP1) and TNF receptor-associated factor 2 (TRAF2). The latter employs the Transforming Growth Factor beta (TGF-β) activated kinase 1 (TAK1) (whose activity is directly regulated by K63-linked polyubiquitination) and TAB1 and TAB2 complex to phosphorylate and activate the IKK signalosome, which phosphorylates IκB that dissociates from NF-κB. NF-κB translocates to the nucleus to induce expression of several genes that participate in inflammation and immunity.
Mentions: The Imd effect was identified by the severely impacted immune phenotypes produced by Drosophila mutants in the intracellular adaptor protein Imd, which interacts with the Drosophila Fas-associated death domain ortholog (dFADD) that binds to Death related ced-3/Nedd2-like caspase (DREDD). Imd is cleaved by DREDD and is subsequently activated by K63-ubiquitination (Paquette et al., 2010). Fly mutants for Imd are characterized by the lack of AMP production and an increased susceptibility to Gram-negative bacteria (Lemaitre et al., 1995). Similar to the mechanistic structure of the Toll pathway, Imd integrates the activation signal through intracellular adaptor proteins that converge on inducing the nuclear translocation of Relish, another homolog of NF-κB. Relish is activated by Immune Response Deficient 5 (IRD5; IKKβ homolog) and Kenny (Key; IKKγ homolog) which form the fly IKK signalosome that is phosphorylated and activated by the TAK1/TAB2 complex (Kleino and Silverman, 2014). The caspase DREDD cleaves Relish, removing the C-terminal inhibitor ankyrin-repeat/IκB-like domain, which remains in the cytoplasm, which allows the Rel DNA-binding domain (Rel68) to translocate to the nucleus where it induces the transcription of target genes. Target genes in the Imd pathway code for AMPs such as Diptericin and Cecropin, which act against Gram-negative bacteria (Figure 2A). The insect Imd pathway is homologous to the mammalian TNF signaling pathway based on the intracellular mechanisms, although the recognition receptors are different (Lemaitre and Hoffmann, 2007). In mammals, trimeric forms of TNF bind and activate TNF receptor 1 and 2 (TNFR1, TNFR2) cytoplasmic receptors that recruit a cytoplasmic complex composed of tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD), RIP1 and TRAF2 that activates the IKK signalosome via the TAK1/TAB1/TAB2 complex leading to NF-κB translocation and transcriptional induction of genes that modulate inflammation and immune function (Figure 2B). Imd is highly homologous to the mammalian RIP1, which binds to the cytoplasmic domain of the TNFR (Hsu et al., 1996). Both Imd and TNFR signaling induce the recruitment of adaptor proteins through death domain interactions, which results in a phosphorylation cascade to induce NF-κB-mediated transcriptional activation of antibacterial molecules and cytokines (Georgel et al., 2001). Therefore, while the receptor mechanisms are not inherently homologous, they are critically important to the integration of information that is transduced to their homologous intracellular counterparts, which illuminates key parallels between insect and mammalian innate immune systems.

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