A shorter splicing isoform antagonizes ZBP1 to modulate cell death and inflammatory responses.

Z-DNA-binding protein 1 (ZBP1) is an interferon-inducible sensor of Z-DNA and Z-RNA, which has emerged as a critical regulator of cell death and inflammation. ZBP1 binds Z-DNA and Z-RNA via its Zα domains, and signals by engaging RIPK3 and RIPK1 via its RIP homotypic interaction motifs (RHIMs). Here, we show that mice express an alternatively-spliced shorter ZBP1 isoform (ZBP1-S), which harbours the Zα domains but lacks the RHIMs, and acts as an endogenous inhibitor of the full-length protein (ZBP1-L).

ADAR1 averts fatal type I interferon induction by ZBP1.

Mutations of the ADAR1 gene encoding an RNA deaminase cause severe diseases associated with chronic activation of type I interferon (IFN) responses, including Aicardi-Goutières syndrome and bilateral striatal necrosis. The IFN-inducible p150 isoform of ADAR1 contains a Zα domain that recognizes RNA with an alternative left-handed double-helix structure, termed Z-RNA. Hemizygous ADAR1 mutations in the Zα domain cause type I IFN-mediated pathologies in humans and mice; however, it remains unclear how the interaction of ADAR1 with Z-RNA prevents IFN activation.

Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation.

Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis.

Design of potent Mincle signalling agonists based on an alkyl β-glucoside template.

The innate immune receptor Mincle senses lipid-based molecules derived from pathogens, commensals and altered self. Based on emerging structure-activity relationships we design simple alkyl 6-O-acyl-β-d-glucosides that are effective agonists of Mincle and signal with potency on par with the prototypical ligand trehalose dimycolate.

Mincle: 20 years of a versatile sensor of insults.

Macrophage-inducible C-type lectin, better known as Mincle, is a member of the C-type lectin receptor family and is encoded by Clec4e. Mincle was an orphan receptor for a long time after having been discovered as a lipopolysaccharide-induced protein, yet later an adjuvant glycolipid in mycobacteria-trehalose dimycolate-was identified as a ligand. Ligands for Mincle were also found existing in bacteria, fungi and even mammals.

High affinity sugar ligands of C-type lectin receptor langerin.

Background: Langerin, a C-type lectin receptor (CLR) expressed in a subset of dendritic cells (DCs), binds to glycan ligands for pathogen capture and clearance. Previous studies revealed that langerin has an unusual binding affinity toward 6-sulfated galactose (Gal), a structure primarily found in keratan sulfate (KS). However, details and biological outcomes of this interaction have not been characterized.

Lipidated Brartemicin Analogues Are Potent Th1-Stimulating Vaccine Adjuvants.

Effective Th1-stimulating vaccine adjuvants typically activate antigen presenting cells (APCs) through pattern recognition receptors (PRRs). Macrophage inducible C-type lectin (Mincle) is a PRR expressed on APCs and has been identified as a target for Th1-stimulating adjuvants. Herein, we report on the synthesis and adjuvanticity of rationally designed brartemicin analogues containing long-chain lipids and demonstrate that they are potent Mincle agonists that activate APCs to produce inflammatory cytokines in a Mincle-dependent fashion.

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity.

Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens.

Lipid structure influences the ability of glucose monocorynomycolate to signal through Mincle.

Mincle (macrophage-inducible C-type lectin) is a C-type lectin receptor that provides the capacity for immune sensing of a range of pathogen- and commensal-derived glycolipids. Mincle can recognize mycolic and/or corynomycolic acid esters of trehalose, glycerol and glucose from mycobacteria and corynebacteria. While simple straight-chain long fatty acids (e.

Total synthesis of a cyclopropane-fatty acid α-glucosyl diglyceride from Lactobacillus plantarum and identification of its ability to signal through Mincle.

We report a concise synthesis of glycolipid GL1 from Lactobacillus plantarum commencing from methyl α-d-glucopyroside. A Jacobsen hydrolytic kinetic resolution is used to generate a diastereomerically-pure glycidyl glucoside that was elaborated to the diglyceride by stepwise brominolysis, acylation with oleoyl chloride, and bromide-substitution by the tetrabutylammonium salt of 9S,10R-dihydrosterculic acid. GL1 and analogues were shown to signal through the glycolipid pattern recognition receptor Mincle.

Macrophage-inducible C-type lectin Mincle-expressing dendritic cells contribute to control of splenic Mycobacterium bovis BCG infection in mice.

The macrophage-inducible C-type lectin Mincle has recently been identified to be a pattern recognition receptor sensing mycobacterial infection via recognition of the mycobacterial cell wall component trehalose-6',6-dimycolate (TDM). However, its role in systemic mycobacterial infections has not been examined so far. Mincle-knockout (KO) mice were infected intravenously with Mycobacterium bovis BCG to mimic the systemic spread of mycobacteria under defined experimental conditions.

Identification of residues required for stalled-ribosome rescue in the codon-independent release factor YaeJ.

The YaeJ protein is a codon-independent release factor with peptidyl-tRNA hydrolysis (PTH) activity, and functions as a stalled-ribosome rescue factor in Escherichia coli. To identify residues required for YaeJ function, we performed mutational analysis for in vitro PTH activity towards rescue of ribosomes stalled on a non-stop mRNA, and for ribosome-binding efficiency. We focused on residues conserved among bacterial YaeJ proteins.

Characteristics of aggressive variants in T1a renal cell carcinoma.

Purpose: To explore factors associated with metastasis and prognosis in T1a renal cell carcinoma (RCC).

Methods: We retrospectively reviewed 451 cases of sporadic T1aRCC among 1,060 patients admitted to the Department of Urology at Hamamatsu University Hospital and affiliated hospitals between 1978 and 2007. Clinicopathological factors were analyzed for metastatic and prognostic risks.