A Unique Feature of Toll/IL-1 Receptor Domain-Containing Adaptor Protein Is Partially Responsible for Lipopolysaccharide Insensitivity in Zebrafish with a Highly Conserved Function of Myd88

Liu, Qing; Li, Mengzhen; Shan, Fan; Lin, Yiqun; Lin, Bin; Luo, Fang; Zhang, Chenxu; Chen, Shangwu; Li, Yingqiu; Xu, Anlong

doi:10.4049/jimmunol.0903147

Cited by 35 publications

(19 citation statements)

References 44 publications

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“…In fact, there have been other reports that illustrate similar findings, that indeed MyD88 is present in aggregate structures in the cytoplasm (23,25). Furthermore, this seems to be a characteristic of MyD88 that is conserved across species (29). A recent study by Liu et al show that zebrafish MyD88 is also expressed as large condensed spots in the cytoplasm of cells, and this observation is reproducible in different cell lines.…”

Section: Discussionsupporting

confidence: 57%

Natural Loss-of-function Mutation of Myeloid Differentiation Protein 88 Disrupts Its Ability to Form Myddosomes

Nagpal

Plantinga

Sirois

et al. 2011

Journal of Biological Chemistry

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Myeloid differentiation protein 88 (MyD88) is a key signaling adapter in Toll-like receptor (TLR) signaling. MyD88 is also one of the most polymorphic adapter proteins. We screened the reported nonsynonymous coding mutations in MyD88 to identify variants with altered function. In reporter assays, a death domain variant, S34Y, was found to be inactive. Importantly, in reconstituted macrophage-like cell lines derived from knockout mice, MyD88 S34Y was severely compromised in its ability to respond to all MyD88-dependent TLR ligands. Unlike wildtype MyD88, S34Y is unable to form distinct foci in the cells but is present diffused in the cytoplasm. We observed that IRAK4 co-localizes with MyD88 in these aggregates, and thus these foci appear to be "Myddosomes." The MyD88 S34Y lossof-function mutant demonstrates how proper cellular localization of MyD88 to the Myddosome is a feature required for MyD88 function.Toll-like receptors (TLRs) 4 are a part of the innate immune system and play a critical role in host defense against a variety of pathogens. Ten functional TLRs in humans and 12 in mice have been identified to date (1). Each TLR recognizes different categories of evolutionarily conserved patterns called pathogen-associated molecular patterns in microbes. For example, TLR4 recognizes lipopolysaccharide (LPS) from the cell walls of bacteria, whereas CpG-rich DNA from bacteria and viruses acts as the ligand for TLR9.Much of the diversity of TLR pathways can be attributed to differential use of the TIR domain-containing adapter proteins. There are four adapter proteins: MyD88, MyD88 adapter-like (Mal), also called TIR domain-containing adapter protein (TIRAP), TIR domain-containing adapter-inducing interferon-␤ (TRIF), and TRIF-related adaptor molecule (TRAM).MyD88 is a key adapter protein involved in signaling from all of the TLRs except TLR3 and the TRIF-mediated arm of TLR4 signaling. Thus, depending on its use, TLR pathways can be divided into MyD88-dependent and MyD88-independent pathways. The engagement of a particular TLR by its ligand triggers a signaling cascade, which culminates in the secretion of various proinflammatory cytokines and interferons.MyD88 is a 296-amino acid protein with a modular domain structure. In addition to the N-terminal TIR domain, it has a death domain at its C terminus. The crystal structure of the MyD88 death domain has recently been resolved, and it reveals that MyD88 exists in oligomeric form in solution (2). These oligomers of MyD88 can recruit the death domains of interleukin-1 receptor-associated kinase (IRAK)4 and IRAK2 to form a ternary complex called the Myddosome.The importance of single nucleotide polymorphisms (SNPs) in TLR-related proteins has recently been brought to the forefront, with many studies implicating SNPs in disease susceptibility and outcome (3-7). Mal and MyD88 are the most polymorphic of the four adapter proteins, and Mal has received the most scrutiny in this regard (8 -10). However, other than a study by Von Bernuth et al., where children with MyD88 ...

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Section: Discussionsupporting

confidence: 57%

Natural Loss-of-function Mutation of Myeloid Differentiation Protein 88 Disrupts Its Ability to Form Myddosomes

Nagpal

Plantinga

Sirois

et al. 2011

Journal of Biological Chemistry

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“…Rebl et al, 2009). Recently, Liu et al (2010) detected experimentally that TLRs need to use MyD88 directly to convert signalling to NF-B and IFN-␤ in zebrafish, thus confirmed the downstream of MyD88-dependent TLR signal pathway was conserved in zebrafish and mammals. Earlier investigation showed that MyD88-knock-out embryos of zebrafish harboured 100-1000-fold more bacteria than the wild type MyD88 embryos when injected with the pathogenic bacterium Salmonella enterica, revealing the role of MyD88 in fish immune response (van der Sar et al, 2006).…”

Section: Discussionmentioning

confidence: 80%

“…It was also shown that in Japanese flounder the number of MyD88-expressing cells increased in spleen and kidney after the infection of Edwardsiella tarda, and the MyD88 expression was further up-regulated in peripheral blood leucocytes when stimulated with LPS, Poly(I:C) and peptidoglycan (Takano et al, 2006). Although the bacterial number was not quantified in the V. alginolyticus-infected fish, the increased expression of TLR1 and TLR2, as well as MyD88 genes in spleen and kidney of the orange-spotted groupers injected with V. alginolyticus and with LPS and Poly(I:C) may in fact imply, as shown in Japanese flounder and in zebrafish (Takano et al, 2006;Liu et al, 2010), the activation of MyD88-dependent pathway in the grouper, leading to the induction of IL-1␤. Recent study also reported the increased expression of IL-1␤ via TLR2 in carp macrophages when stimulated with peptidoglycan (Ribeiro et al, 2010).…”

Section: Discussionmentioning

confidence: 98%

Cloning and expression of Toll-like receptors 1 and 2 from a teleost fish, the orange-spotted grouper Epinephelus coioides

Wei

Pan

Chang

et al. 2011

Veterinary Immunology and Immunopathology

106

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“…Some of these components are known to trigger the activation of Toll-like receptors (TLRs) or activate intracellular signalling molecules, including the nucleotide-binding-domain-and leucine-rich-repeat-containing family proteins (NLRs). The importance of these pathways is being defined in the zebrafish, and their contribution to host defence against infectious agents in vertebrates is being dissected in detail (Meijer et al, 2004; van der Sar et al, 2006; Hall et al, 2009; Sepulcre et al, 2009; Stockhammer et al, 2009; Sullivan et al, 2009; Liu et al, 2010; Palti, 2011). Zebrafish genetic knockouts of components of these pathways are eagerly awaited.…”

Section: Granulocytes: the First Wavementioning

confidence: 99%

A model 450 million years in the making: zebrafish and vertebrate immunity

Renshaw

Trede

2012

Disease Models &Amp; Mechanisms

316

266

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Since its first splash 30 years ago, the use of the zebrafish model has been extended from a tool for genetic dissection of early vertebrate development to the functional interrogation of organogenesis and disease processes such as infection and cancer. In particular, there is recent and growing attention in the scientific community directed at the immune systems of zebrafish. This development is based on the ability to image cell movements and organogenesis in an entire vertebrate organism, complemented by increasing recognition that zebrafish and vertebrate immunity have many aspects in common. Here, we review zebrafish immunity with a particular focus on recent studies that exploit the unique genetic and in vivo imaging advantages available for this organism. These unique advantages are driving forward our study of vertebrate immunity in general, with important consequences for the understanding of mammalian immune function and its role in disease pathogenesis.

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A Unique Feature of Toll/IL-1 Receptor Domain-Containing Adaptor Protein Is Partially Responsible for Lipopolysaccharide Insensitivity in Zebrafish with a Highly Conserved Function of Myd88

Abstract: Material

Cited by 35 publications

References 44 publications

Natural Loss-of-function Mutation of Myeloid Differentiation Protein 88 Disrupts Its Ability to Form Myddosomes

Natural Loss-of-function Mutation of Myeloid Differentiation Protein 88 Disrupts Its Ability to Form Myddosomes

Cloning and expression of Toll-like receptors 1 and 2 from a teleost fish, the orange-spotted grouper Epinephelus coioides

A model 450 million years in the making: zebrafish and vertebrate immunity

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