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Subverting Toll-Like Receptor Signaling by Bacterial Pathogens.

McGuire VA, Arthur JS - Front Immunol (2015)

Bottom Line: These pathways are critical for mounting an effective immune response.In order to evade detection and promote virulence, many pathogens subvert the host immune response by targeting components of these signal transduction pathways.Understanding the elaborate strategies that pathogens employ to subvert the immune response not only highlights the importance of these proteins in mounting effective immune responses, but may also identify novel approaches for treatment or prevention of infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee , Dundee , UK.

ABSTRACT
Pathogenic bacteria are detected by pattern-recognition receptors (PRRs) expressed on innate immune cells, which activate intracellular signal transduction pathways to elicit an immune response. Toll-like receptors are, perhaps, the most studied of the PRRs and can activate the mitogen-activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB) pathways. These pathways are critical for mounting an effective immune response. In order to evade detection and promote virulence, many pathogens subvert the host immune response by targeting components of these signal transduction pathways. This mini-review highlights the diverse mechanisms that bacterial pathogens have evolved to manipulate the innate immune response, with a particular focus on those that target MAPK and NF-κB signaling pathways. Understanding the elaborate strategies that pathogens employ to subvert the immune response not only highlights the importance of these proteins in mounting effective immune responses, but may also identify novel approaches for treatment or prevention of infection.

No MeSH data available.


Related in: MedlinePlus

Blockade of MAPK and NFκB signaling by bacterial effectors. TLR signaling is initiated by the recruitment of adaptor proteins to the TIR domain of the receptor. Recruitment of MyD88 facilitates Myddosome formation through binding of IRAK4, IRAK1, and IRAK2. IRAKs bind to and recruit the E3 ubiquitin ligase TRAF6, which – perhaps with input from other E3s – generates lysine-63 (K63) linked polyubiquitin chains. K63 linked polyubiquitin chains are used as a substrate by LUBAC to form M1-K63 hybrid polyubiquitin chains. K63 and M1-K63 polyubiquitin chains are necessary for downstream signaling mediated by TAK1. TAK1 phosphorylates and activates IKKα/β, which form the IKK complex together with NEMO/IKKγ. The IKK complex phosphorylates IκBα, resulting in its K48-linked polyubiquitination and proteasomal degradation, which releases the p65 NFκB subunit from inhibition. The IKK complex also phosphorylates p105, generating the p50 NFκB subunit, and enabling the active p50-p65 NFκB dimer to translocate to the nucleus. TAK1 also controls activation of the ERK1/2, p38, and JNK MAPK pathways by acting as a MAP3K for the p38 and JNK pathways and controlling the activation of ERK1/2 via Tpl2. Phosphorylation of p105 by the IKK complex releases Tpl2 from inhibition, allowing Tpl2 to activate ERK1/2 signaling. MAPKs phosphorylate their own downstream targets including other kinases and transcription factors that regulate transcription. Activation of TLR3 and TLR4 can also recruit the TRIF adaptor, which activates NFκB and MAPK signaling via both Receptor Interacting Protein 1 (RIP1) and TRAF6 upstream of TAK1, and activates IRF3 via IKKϵ and Tank-binding kinase 1 (TBK1). Bacterial effectors block signaling by interfering with different components of the signaling cascades, as indicated in the figure.
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Figure 1: Blockade of MAPK and NFκB signaling by bacterial effectors. TLR signaling is initiated by the recruitment of adaptor proteins to the TIR domain of the receptor. Recruitment of MyD88 facilitates Myddosome formation through binding of IRAK4, IRAK1, and IRAK2. IRAKs bind to and recruit the E3 ubiquitin ligase TRAF6, which – perhaps with input from other E3s – generates lysine-63 (K63) linked polyubiquitin chains. K63 linked polyubiquitin chains are used as a substrate by LUBAC to form M1-K63 hybrid polyubiquitin chains. K63 and M1-K63 polyubiquitin chains are necessary for downstream signaling mediated by TAK1. TAK1 phosphorylates and activates IKKα/β, which form the IKK complex together with NEMO/IKKγ. The IKK complex phosphorylates IκBα, resulting in its K48-linked polyubiquitination and proteasomal degradation, which releases the p65 NFκB subunit from inhibition. The IKK complex also phosphorylates p105, generating the p50 NFκB subunit, and enabling the active p50-p65 NFκB dimer to translocate to the nucleus. TAK1 also controls activation of the ERK1/2, p38, and JNK MAPK pathways by acting as a MAP3K for the p38 and JNK pathways and controlling the activation of ERK1/2 via Tpl2. Phosphorylation of p105 by the IKK complex releases Tpl2 from inhibition, allowing Tpl2 to activate ERK1/2 signaling. MAPKs phosphorylate their own downstream targets including other kinases and transcription factors that regulate transcription. Activation of TLR3 and TLR4 can also recruit the TRIF adaptor, which activates NFκB and MAPK signaling via both Receptor Interacting Protein 1 (RIP1) and TRAF6 upstream of TAK1, and activates IRF3 via IKKϵ and Tank-binding kinase 1 (TBK1). Bacterial effectors block signaling by interfering with different components of the signaling cascades, as indicated in the figure.

Mentions: Stimulation of all TLRs activates the mitogen-activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB) signaling pathways, both of which are critical for an effective immune response. The current understanding of the signaling events that trigger MAPK and NF-κB activation in response to TLR stimulation have been reviewed recently (1–4), but is summarized below and in Figure 1.


Subverting Toll-Like Receptor Signaling by Bacterial Pathogens.

McGuire VA, Arthur JS - Front Immunol (2015)

Blockade of MAPK and NFκB signaling by bacterial effectors. TLR signaling is initiated by the recruitment of adaptor proteins to the TIR domain of the receptor. Recruitment of MyD88 facilitates Myddosome formation through binding of IRAK4, IRAK1, and IRAK2. IRAKs bind to and recruit the E3 ubiquitin ligase TRAF6, which – perhaps with input from other E3s – generates lysine-63 (K63) linked polyubiquitin chains. K63 linked polyubiquitin chains are used as a substrate by LUBAC to form M1-K63 hybrid polyubiquitin chains. K63 and M1-K63 polyubiquitin chains are necessary for downstream signaling mediated by TAK1. TAK1 phosphorylates and activates IKKα/β, which form the IKK complex together with NEMO/IKKγ. The IKK complex phosphorylates IκBα, resulting in its K48-linked polyubiquitination and proteasomal degradation, which releases the p65 NFκB subunit from inhibition. The IKK complex also phosphorylates p105, generating the p50 NFκB subunit, and enabling the active p50-p65 NFκB dimer to translocate to the nucleus. TAK1 also controls activation of the ERK1/2, p38, and JNK MAPK pathways by acting as a MAP3K for the p38 and JNK pathways and controlling the activation of ERK1/2 via Tpl2. Phosphorylation of p105 by the IKK complex releases Tpl2 from inhibition, allowing Tpl2 to activate ERK1/2 signaling. MAPKs phosphorylate their own downstream targets including other kinases and transcription factors that regulate transcription. Activation of TLR3 and TLR4 can also recruit the TRIF adaptor, which activates NFκB and MAPK signaling via both Receptor Interacting Protein 1 (RIP1) and TRAF6 upstream of TAK1, and activates IRF3 via IKKϵ and Tank-binding kinase 1 (TBK1). Bacterial effectors block signaling by interfering with different components of the signaling cascades, as indicated in the figure.
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Figure 1: Blockade of MAPK and NFκB signaling by bacterial effectors. TLR signaling is initiated by the recruitment of adaptor proteins to the TIR domain of the receptor. Recruitment of MyD88 facilitates Myddosome formation through binding of IRAK4, IRAK1, and IRAK2. IRAKs bind to and recruit the E3 ubiquitin ligase TRAF6, which – perhaps with input from other E3s – generates lysine-63 (K63) linked polyubiquitin chains. K63 linked polyubiquitin chains are used as a substrate by LUBAC to form M1-K63 hybrid polyubiquitin chains. K63 and M1-K63 polyubiquitin chains are necessary for downstream signaling mediated by TAK1. TAK1 phosphorylates and activates IKKα/β, which form the IKK complex together with NEMO/IKKγ. The IKK complex phosphorylates IκBα, resulting in its K48-linked polyubiquitination and proteasomal degradation, which releases the p65 NFκB subunit from inhibition. The IKK complex also phosphorylates p105, generating the p50 NFκB subunit, and enabling the active p50-p65 NFκB dimer to translocate to the nucleus. TAK1 also controls activation of the ERK1/2, p38, and JNK MAPK pathways by acting as a MAP3K for the p38 and JNK pathways and controlling the activation of ERK1/2 via Tpl2. Phosphorylation of p105 by the IKK complex releases Tpl2 from inhibition, allowing Tpl2 to activate ERK1/2 signaling. MAPKs phosphorylate their own downstream targets including other kinases and transcription factors that regulate transcription. Activation of TLR3 and TLR4 can also recruit the TRIF adaptor, which activates NFκB and MAPK signaling via both Receptor Interacting Protein 1 (RIP1) and TRAF6 upstream of TAK1, and activates IRF3 via IKKϵ and Tank-binding kinase 1 (TBK1). Bacterial effectors block signaling by interfering with different components of the signaling cascades, as indicated in the figure.
Mentions: Stimulation of all TLRs activates the mitogen-activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB) signaling pathways, both of which are critical for an effective immune response. The current understanding of the signaling events that trigger MAPK and NF-κB activation in response to TLR stimulation have been reviewed recently (1–4), but is summarized below and in Figure 1.

Bottom Line: These pathways are critical for mounting an effective immune response.In order to evade detection and promote virulence, many pathogens subvert the host immune response by targeting components of these signal transduction pathways.Understanding the elaborate strategies that pathogens employ to subvert the immune response not only highlights the importance of these proteins in mounting effective immune responses, but may also identify novel approaches for treatment or prevention of infection.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee , Dundee , UK.

ABSTRACT
Pathogenic bacteria are detected by pattern-recognition receptors (PRRs) expressed on innate immune cells, which activate intracellular signal transduction pathways to elicit an immune response. Toll-like receptors are, perhaps, the most studied of the PRRs and can activate the mitogen-activated protein kinase (MAPK) and Nuclear Factor-κB (NF-κB) pathways. These pathways are critical for mounting an effective immune response. In order to evade detection and promote virulence, many pathogens subvert the host immune response by targeting components of these signal transduction pathways. This mini-review highlights the diverse mechanisms that bacterial pathogens have evolved to manipulate the innate immune response, with a particular focus on those that target MAPK and NF-κB signaling pathways. Understanding the elaborate strategies that pathogens employ to subvert the immune response not only highlights the importance of these proteins in mounting effective immune responses, but may also identify novel approaches for treatment or prevention of infection.

No MeSH data available.


Related in: MedlinePlus