Emerging Principles Governing Signal Transduction by Pattern-Recognition Receptors: Table 1.

Kagan, Jonathan C.; Barton, Gregory M.

doi:10.1101/cshperspect.a016253

Cited by 44 publications

(34 citation statements)

References 124 publications

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“…As noted above, TLRs themselves do not determine the subcellular sites where signal transduction initiates. Instead, TAXI proteins move ligands and TLRs from subcellular sites of ligand recognition to sites of signal initiation . But what determines the sites of signaling?…”

Section: Sorting Adaptor Proteins: Landmarks That Determine the Subcementioning

confidence: 99%

Microbe‐inducible trafficking pathways that control Toll‐like receptor signaling

Kagan

2016

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The receptors of the mammalian innate immune system are designed for rapid microbial detection, and are located in organelles that are conducive to serve these needs. However, emerging evidence indicates that the sites of microbial detection are not the sites of innate immune signal transduction. Rather, microbial detection triggers the movement of receptors to regions of the cell where factors called sorting adaptors detect active receptors and promote downstream inflammatory responses. These findings highlight the critical role that membrane trafficking pathways play in the initiation of innate immunity to infection. In this review, we describe pathways that promote the microbe-inducible endocytosis of Toll-like Receptors (TLRs), and the microbe-inducible movement of TLRs between intracellular compartments. We highlight a new class of proteins called Transporters Associated with the eXecution of Inflammation (TAXI), which have the unique ability to transport TLRs and their microbial ligands to signaling-competent regions of the cell, and we discuss the means by which the subcellular sites of signal transduction are defined.

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Section: Sorting Adaptor Proteins: Landmarks That Determine the Subcementioning

confidence: 99%

Microbe‐inducible trafficking pathways that control Toll‐like receptor signaling

Kagan

2016

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“…TIRAP senses active ( i.e. dimerized) TLR4 through interactions between the Toll/IL-1 Receptor (TIR) domains present in each of these proteins (Kagan and Barton, 2014). These TIR-TIR interactions prompt TIRAP to assemble a higher order filamentous structure called the myddosome, which consists of the signaling adaptor MyD88 and several IRAK family kinases (Bonham et al, 2014; Lin et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…The importance of the endosome-specific signaling pathway is underscored by the fact that most TLR4-inducible genes (even those activated by MyD88) are dependent on TRIF (Yamamoto et al, 2003). Thus, in the case of TLR4, a dominant site of TLR4 signal transduction (endosomes) is distinct from the site of ligand binding (plasma membrane) (Kagan and Barton, 2014). …”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Toll-like Receptor 4 Endocytosis Reveal a Common Immune-Evasion Strategy Used by Pathogenic and Commensal Bacteria

et al. 2015

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Microbe-induced receptor trafficking has emerged as an essential means to promote innate immune signal transduction. Upon detection of bacterial lipopolysaccharides (LPS), CD14 induces an inflammatory endocytosis pathway that delivers Toll-like Receptor 4 (TLR4) to endosomes. Although several regulators of CD14-dependent TLR4 endocytosis have been identified, the cargo selection mechanism during this process remains unknown. We reveal that, in contrast to classic cytosolic interactions that promoted the endocytosis of transmembrane receptors, TLR4 was selected as cargo for inflammatory endocytosis entirely through extracellular interactions. Mechanistically, the extracellular protein MD-2 bound to and dimerized TLR4 in order to promote this endocytic event. Our analysis of LPS variants from human pathogens and gut commensals revealed a common mechanism by which bacteria prevent inflammatory endocytosis. We suggest that evasion of CD14-dependent endocytosis is an attribute that transcends the concept of pathogenesis, and may be a fundamental feature of bacteria that inhabit eukaryotic hosts.

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“…Rather, receptors of the NLR, RLR and ALR family are responsible. The central difference between these receptors and the TLRs and Dectins is that the former group surveys the intracellular (usually cytosolic) space for microbial products (Kagan and Barton, 2014). …”

Section: Pamps From Virulent Microbes Induce Diverse Activation Statementioning

confidence: 99%

Innate Immune Receptors as Competitive Determinants of Cell Fate

Franz

Kagan

2017

Molecular Cell

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Infections can cause a multitude of stresses on the host and microbe. To detect potential infections, the mammalian immune system utilizes several families of pattern recognition receptors, which survey the intracellular and extracellular environments for microbial products. Members of each receptor family induce antimicrobial effector responses, which include inflammatory cytokine or interferon expression, downregulation of protein synthesis or host cell death. In this Review, we discuss the benefits of each of these innate immune responses. We highlight how non-infectious bacteria and viruses typically activate a single family of receptors, which results in a predictable host response. Infections with virulent pathogens, in contrast, may activate receptors from distinct families. As each receptor family may induce responses that antagonize or synergize with the activities of another family, cell fate decisions during pathogenic encounters are unpredictable. Understanding the antagonistic antimicrobial activities of the innate immune system should provide insight into how cell fate decisions are made during infections, and potentially during other environmental stresses.

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Emerging Principles Governing Signal Transduction by Pattern-Recognition Receptors: Table 1.

Cited by 44 publications

References 124 publications

Microbe‐inducible trafficking pathways that control Toll‐like receptor signaling

Microbe‐inducible trafficking pathways that control Toll‐like receptor signaling

Mechanisms of Toll-like Receptor 4 Endocytosis Reveal a Common Immune-Evasion Strategy Used by Pathogenic and Commensal Bacteria

Innate Immune Receptors as Competitive Determinants of Cell Fate

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