The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade

Heinz, Leonhard X.; Rebsamen, Manuele; Rossi, Daniele; Staehli, Francesco; Schroder, Kate; Quadroni, Manfredo; Groß, Olaf; Schneider, Pascal; Tschopp, Jürg

doi:10.1038/cdd.2011.147

Cited by 27 publications

(22 citation statements)

References 41 publications

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“…IL-1RAcPb is a unique receptor expressed on neurons, and its expression implicates activation of certain signalling pathways, such as p38 MAPK, but not NF-κB; it has even been observed that this alternative signalling pathway is independent on MyD88, IRAK1 and TRAF6 [ 59 , 60 ]. Moreover, Heinz et al reported a new molecule known as Unc5CL; this protein contains death domains (DD) similarly to those found in MyD88 [ 61 ]. Unc5CL is considered as a pro-inflammatory signalling inducer and involves recruitment of IRAK1, IRAK4, TRAF6 and converges in NF-κB and JNK activation in a MyD88-independent manner [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Heinz et al reported a new molecule known as Unc5CL; this protein contains death domains (DD) similarly to those found in MyD88 [ 61 ]. Unc5CL is considered as a pro-inflammatory signalling inducer and involves recruitment of IRAK1, IRAK4, TRAF6 and converges in NF-κB and JNK activation in a MyD88-independent manner [ 61 ]. Currently, there are not reports in which these new molecules have been reported in PBMC; however, the possibility to perform future studies that elucidate this observation remains open.…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor

et al. 2020

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The inflammatory process implicates homeostasis disruption and increased production of inflammatory mediators. Myeloid differentiation primary response 88 (MyD88) is an essential protein recruited after lipopolysaccharide (LPS) and interleukin (IL)-1β stimulation, a process that converges in nuclear factor kappa B (NF-κB) activation, as well as a transcription of several genes of both pro- and anti-inflammatory cytokines. The inhibition of MyD88 has shown efficacy by decrease inflammatory response, and has demonstrated potential application as a therapeutic target in chronic diseases. In this study, we investigate the effect of MyD88 dimerisation inhibitor ST2825 on cytokine production from rhIL-1β and LPS-stimulated peripheral blood mononuclear cells (PBMC) from healthy blood donors (HBD). ST2825 significantly downregulates the production of IFN-γ, IL-6, IL-12, IL-2, IL-15, IL-7, VEGF, IL-1Ra, IL-4, IL-5, IL-13 and IL-9 (p < 0.05) in LPS-stimulated PBMC. Moreover, ST2825 had a relatively low impact on IL-1β signalling pathway inhibition, showing that only a few specific cytokines, such as IFN-γ and IL-1Ra, are inhibited in rhIL-1β-stimulated PBMC (p < 0.01). In conclusion, MyD88 dimerisation inhibitor ST2825 showed high efficacy by inhibiting pro- and anti-inflammatory cytokine production in LPS-stimulated PBMC. Moreover, although rhIL-1β induced a sustained cytokine production (p < 0.05), ST2825 did not show a significant effect in the secretion of neither pro- nor anti-inflammatory cytokines in rhIL-1β-stimulated PBMC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor

et al. 2020

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“…2). However, the experimentally verified autoproteolytic sites in PIDD [25] and UNC5C-like protein [26] are present in the equivalent positions with GAIN and Nup98 C-terminal domain (Fig. 2).…”

Section: Homologous Relationship Of Gain Zu5 and Nup98 C-terminal Domentioning

confidence: 99%

“…UNC5A, UNC5B, UNC5C and UNC5D have similar extracellular domain architectures. In contrast, UNC5C-like protein has only a very short extracellular terminus and contains an autoproteolytic site of HFS motif in the ZU5 domain [26]. Others are cytoplasmic proteins and have some variation of the general ZU5-UPA-DD domain organization.…”

Section: Domain Architectures and Phylogenetic Distribution Of Gain-bmentioning

confidence: 99%

“…This ZU5 domain is thought to be responsible for interacting with cytoskeletal dynamics regulatory protein kinase MRCKβ and targeting it to the leading edge of migrating cells [24]. Although no ZU5 domains with available structures are processed posttranslationally, p53-induced protein with a death domain (PIDD) and UNC5C-like protein with ZU5 domains are both cleaved by autoproteolysis constitutively both at HF↓S sites [25, 26]. …”

Section: Introductionmentioning

confidence: 99%

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An Ancient Autoproteolytic Domain Found in GAIN, ZU5 and Nucleoporin98

Liao

Pei

Cheng

et al. 2014

Journal of Molecular Biology

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A large family of G protein-coupled receptors (GPCRs) involved in cell adhesion has a characteristic autoproteolysis motif of HLT/S known as the GPCR proteolysis site (GPS). GPS is also shared by polycystic kidney disease (PKD) proteins and it precedes the first transmembrane segment in both families. Recent structural studies have elucidated the GPS to be part of a larger domain named GPCR autoproteolysis inducing (GAIN) domain. Here we demonstrate the remote homology relationships of GAIN domain to ZU5 domain and Nucleoporin98 C-terminal domain by structural and sequence analysis. Sequence homology searches were performed to extend ZU5-like domains to bacteria and archaea, as well as new eukaryotic families. We found the consecutive ZU5-UPA-DD domain organization is commonly used in human cytoplasmic proteins with ZU5 domains, including CARD8 and NLRP1 from the FIIND (Function to Find) family. Another divergent family of extracellular ZU5-like domains was identified in cartilage intermediate layer proteins (CILPs) and FAM171 proteins. Current diverse families of GAIN domain subdomain B, ZU5 and Nup98 C-terminal domain likely evolved from an ancient autoproteolytic domain with a HFS motif. The autoproteolytic site was kept intact in Nup98, PIDD and UNC5C-like, deteriorated in many ZU5 domains and changed in GAIN and FIIND. Deletion of the strand after the cleavage site was observed in ZO-1 and some Nup98 homologs. These findings link several autoproteolytic domains, extend our understanding of GAIN domain origination in adhesion GPCRs and provide insights into the evolution of an ancient autoproteolytic domain.

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Structure and evolution of neuronal wiring receptors and ligands

Cortés

Pak

Özkan

2022

Developmental Dynamics

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One of the fundamental properties of a neuronal circuit is the map of its connections. The cellular and developmental processes that allow for the growth of axons and dendrites, selection of synaptic targets, and formation of functional synapses use neuronal surface receptors and their interactions with other surface receptors, secreted ligands, and matrix molecules. Spatiotemporal regulation of the expression of these receptors and cues allows for specificity in the developmental pathways that wire stereotyped circuits. The families of molecules controlling axon guidance and synapse formation are generally conserved across animals, with some important exceptions, which have consequences for neuronal connectivity. Here, we summarize the distribution of such molecules across multiple taxa, with a focus on model organisms, evolutionary processes that led to the multitude of such molecules, and functional consequences for the diversification or loss of these receptors.

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The death domain-containing protein Unc5CL is a novel MyD88-independent activator of the pro-inflammatory IRAK signaling cascade

Cited by 27 publications

References 41 publications

Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor

Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor

An Ancient Autoproteolytic Domain Found in GAIN, ZU5 and Nucleoporin98

Structure and evolution of neuronal wiring receptors and ligands

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