The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signalling

Flannery, Sinead M.; Bowie, Andrew

doi:10.1016/j.bcp.2010.06.020

Cited by 261 publications

(213 citation statements)

References 101 publications

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“…Recently, pseudokinases have emerged as key regulatory effectors in metazoan signal transduction (35), particularly in mammalian immune signaling (36,37). Although it is difficult to determine the specific role of a catalytically inactive protein, other pseudokinases have been shown to act as molecular scaffolds (38)(39)(40) and thereby, coordinate signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

Reese

Zeiner

Boothroyd

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

242

303

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Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an extraordinarily successful parasite, infecting an estimated 30% of humans worldwide. The outcome of Toxoplasma infection is highly dependent on allelic differences in the large number of effectors that the parasite secretes into the host cell. Here, we show that the largest determinant of the virulence difference between two of the most common strains of Toxoplasma is the ROP5 locus. This is an unusual segment of the Toxoplasma genome consisting of a family of 4-10 tandem, highly divergent genes encoding pseudokinases that are injected directly into host cells. Given their hypothesized catalytic inactivity, it is striking that deletion of the ROP5 cluster in a highly virulent strain caused a complete loss of virulence, showing that ROP5 proteins are, in fact, indispensable for Toxoplasma to cause disease in mice. We find that copy number at this locus varies among the three major Toxoplasma lineages and that extensive polymorphism is clustered into hotspots within the ROP5 pseudokinase domain. We propose that the ROP5 locus represents an unusual evolutionary strategy for sampling of sequence space in which the gene encoding an important enzyme has been (i) catalytically inactivated, (ii) expanded in number, and (iii) subject to strong positive selection. Such a strategy likely contributes to Toxoplasma's successful adaptation to a wide host range and has resulted in dramatic differences in virulence.copy number variation | host-pathogen interaction T he evolutionary pressure on the molecules that form the interface between a pathogenic organism and its host has been likened to an arms race (1, 2) and has been proposed to give rise to highly polymorphic genes such as those that encode host MHC and viral capsid proteins. Whereas most pathogens have a single or restricted range of hosts with which they coevolve, the obligate intracellular parasite Toxoplasma gondii can infect virtually any cell of almost any warm-blooded animal, a remarkable feat from an evolutionary perspective.Different strains of Toxoplasma cause significantly different disease in mice (3) and humans as well (4, 5). In North America and Europe, three strains have grown to dominate Toxoplasma's genetic landscape, and they are characterized by distinct disease outcomes in mice: although a single Type I parasite is uniformly lethal to a mouse, Type II and III parasites have a lethal dose (LD 50 ) ranging from 10 2 to 10 5 (3). Sexual crosses between members of these lineages (Type I × Type III and Type II × Type III) (6, 7) have shown that virulence in mice segregates among F1 progeny (8). This has allowed for the discovery of a number of virulence loci using quantitative trait loci (QTL) mapping (9, 10).Toxoplasma secretes an arsenal of effector proteins into its host cell from specialized secretory organelles termed rhoptries and dense granules (11)(12)(13)(14). Given the selective pressure...

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Section: Discussionmentioning

confidence: 99%

Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

Reese

Zeiner

Boothroyd

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

242

303

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“…Following on from this finding, other IRAKs were discovered and IRAK4 was shown to be the most important receptor--proximal kinase (reviewed in Ref. 75). IRAK1 was shown to interact with TNF receptor--associated factor 6 (TRAF6), which is a member of the TRAF family of proteins that are known to activate the NF--κB pathway.…”

Section: Elucidation Of Tlr Signallingmentioning

confidence: 97%

The history of Toll-like receptors — redefining innate immunity

2013

Self Cite

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The discovery of Toll--like receptors (TLRs) was an important event for immunology research and was recognized as such with the awarding of the 2011 Nobel Prize in Physiology or Medicine to Jules Hoffmann and Bruce Beutler, who, together with Ralph Steinman, the third winner of the 2011 Nobel Prize and the person who discovered the dendritic cell, were pioneers in the field of innate immunity. TLRs have a central role in immunity -in this Timeline article, we describe the landmark findings that gave rise to this important field of research.

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“…Phosphorylated IκBα is targeted for ubiquitin-mediated proteasome degradation, freeing NFκB to translocate to the nucleus and act upon target genes. 34 The TRIF-dependent pathway also leads to NFκB activation. This pathway includes a complex of TRADD and RIP-1, which mediates cleavage of the zymogens capsase-8 and caspase-10 into their active forms, which, in turn, activate NFκB.…”

Section: Pathways Of Activation By Toll-like Receptorsmentioning

confidence: 99%

Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K

Troutman

Bazán²,

Pasare³

2012

Cell Cycle

192

140

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The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signalling

Cited by 261 publications

References 101 publications

Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

The history of Toll-like receptors — redefining innate immunity

Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K

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