Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4.

Neutrophils are peripheral blood-circulating leukocytes that play a pivotal role in host defense against bacterial pathogens which upon activation, they release web-like chromatin structures called neutrophil extracellular traps (NETs). Here, we analyzed and compared the importance of myeloid differentiation factor 88 (MYD88), peptidyl arginine deiminase 4 (PAD4), and gasdermin D (GSDMD) for NET formation in vivo following sepsis and neutrophilia challenge. Injection of lipopolysaccharide (LPS)/E.

Sex- and species-specific contribution of CD99 to T cell costimulation during multiple sclerosis.

Background: Differences in immune responses between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect women, such as multiple sclerosis (MS). MS manifests in more than twice as many women, making sex one of the most important risk factor. However, it is incompletely understood which genes contribute to sex differences in autoimmune incidence.

Lack of a protective effect of the Tmem106b "protective SNP" in the Grn knockout mouse model for frontotemporal lobar degeneration.

Genetic variants in TMEM106B are a common risk factor for frontotemporal lobar degeneration and the most important modifier of disease risk in patients with progranulin (GRN) mutations (FTLD-GRN). TMEM106B is encoding a lysosomal transmembrane protein of unknown molecular function. How it mediates its disease-modifying function remains enigmatic.

The adaptor protein PICK1 targets the sorting receptor SorLA.

SorLA is a member of the Vps10p-domain (Vps10p-D) receptor family of type-I transmembrane proteins conveying neuronal endosomal sorting. The extracellular/luminal moiety of SorLA has a unique mosaic domain composition and interacts with a large number of different and partially unrelated ligands, including the amyloid precursor protein as well as amyloid-β. Several studies support a strong association of SorLA with sporadic and familial forms of Alzheimer's disease (AD).

Revisiting the proteolytic processing of cell adhesion molecule L1.

The important functions of cell adhesion molecule L1 in the nervous system depend on diverse proteolytic enzymes which generate different L1 fragments. It has been reported that cleavage in the third fibronectin type III (FNIII) homologous domain generates the fragments L1-80 and L1-140, while cleavage in the first FNIII domain yields the fragments L1-70 and L1-135. These results raised questions concerning the L1 cleavage sites.

A variant in with a selective IL-11 signaling defect in human and mouse.

The GP130 cytokine receptor subunit encoded by is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in (p.R281Q) in a patient with craniosynostosis and retained deciduous teeth.

Development of phosphatase inhibitor-1 peptides acting as indirect activators of phosphatase 1.

Phosphatase inhibitor-1 (I-1) inhibits the catalytic subunit of protein phosphatase type 1 (PP1c) in its protein kinase A (PKA)-phosphorylated form (I-1(P)). It thereby amplifies PKA signaling, which, in the heart, mediates both beneficial (acute) and adverse (chronic) effects of catecholamines. Genetic deletion of I-1 was associated with protection against catecholamine toxicity, making the PP1c-I-1(P) complex a potential therapeutic target for chronic heart disease.

A multiple sclerosis-associated variant of CBLB links genetic risk with type I IFN function.

Multiple sclerosis (MS) is an autoimmune disease of the CNS, and autoreactive CD4(+) T cells are considered important for its pathogenesis. The etiology of MS involves a complex genetic trait and environmental triggers that include viral infections, particularly the EBV. Among the risk alleles that have repeatedly been identified by genome-wide association studies, three are located near the Casitas B-lineage lymphoma proto-oncogene b gene (CBLB).

Impact of methionine oxidation as an initial event on the pathway of human prion protein conversion.

Prion diseases comprise a group of fatal neurodegenerative disorders characterized by the autocatalytic conversion of the cellular prion protein PrP(C) into the infectious misfolded isoform PrP(Sc). Increasing evidence supports a specific role of oxidative stress in the onset of pathogenesis. Although the associated molecular mechanisms remain to be elucidated in detail, several studies currently suggest that methionine oxidation already detected in misfolded PrP(Sc) destabilizes the native PrP fold as an early event in the conversion pathway.

Nuclear factor I-A represses expression of the cell adhesion molecule L1.

Background: The neural cell adhesion molecule L1 plays a crucial role in development and plasticity of the nervous system. Neural cells thus require precise control of L1 expression.

Results: We identified a full binding site for nuclear factor I (NFI) transcription factors in the regulatory region of the mouse L1 gene.

The murine AE4 promoter predominantly drives type B intercalated cell specific transcription.

AE4 is an anion exchanger almost exclusively expressed in the collecting ducts of the kidney. This very restricted expression prompted us to analyze its transcription in more detail. 5' RACE yielded alternative transcriptional start sites that are predicted to code for N-terminal protein variants.

Transcriptional ERRgamma2-mediated activation is regulated by sentrin-specific proteases.

Modification with SUMOs (small ubiquitin-related modifiers) has emerged as an important means of regulating the activity of transcription factors, often by repressing their activity. The ERRgamma [oestrogen receptor-related receptor gamma; ERR3 or NR3B3 (nuclear receptor subfamily 3, group B, gene3)] is a constitutively active orphan nuclear receptor. A PDSM, (phosphorylation-dependent sumoylation motif) is located in the close vicinity of the N-terminally located ERRgamma2-specific AF-1 (activation function-1).

Germ cell nuclear factor is a repressor of CRIPTO-1 and CRIPTO-3.

The pluripotency of embryonic stem and embryonic carcinoma cells is maintained by the expression of a set of "stemness" genes. Whereas these genes are down-regulated upon induction of differentiation, the germ cell nuclear factor (GCNF) is transiently up-regulated and represses several pluripotency genes. CRIPTO-1, a co-receptor for the morphogen nodal, is strongly expressed in undifferentiated cells and is rapidly down-regulated during retinoic acid-induced differentiation.

The forkhead transcription factor Foxi1 directly activates the AE4 promoter.

Intercalated cells are highly specialized cells within the renal collecting duct epithelium and play an important role in systemic acid-base homoeostasis. Whereas type A intercalated cells secrete protons via an apically localized H+-ATPase, type B intercalated cells secrete HCO3-. Type B intercalated cells specifically express the HCO3-/Cl- exchanger AE4 (anion exchanger 4), encoded by Slc4a9.

Identification of PNRC2 and TLE1 as activation function-1 cofactors of the orphan nuclear receptor ERRgamma.

Estrogen-related receptor gamma (ERRgamma) is an orphan nuclear receptor highly expressed in heart, skeletal muscle, kidney, and brain. To identify activation function-1 (AF-1)-dependent cofactors involved in the transcriptional function of ERRgamma, we screened for human cDNAs coding for proteins that bind to the bacterial expressed AF-1 by biopanning of a phage display library. Phages displaying fusion proteins with full-length PNRC2 (proline-rich nuclear receptor co-regulatory protein 2), already shown to be a cofactor for other nuclear receptors, and with a polypeptide of the bHLH corepressor TLE1 bound to the AF-1 containing bait.

Structure of the murine tenascin-R gene and functional characterisation of the promoter.

The tenascin-R (TN-R) gene encodes a multidomain extracellular matrix glycoprotein belonging to the tenascin family. It is detectable mainly in oligodendrocytes and neuronal subpopulations of the central nervous system. In this report, we describe the structure of the 5'-region of the mouse TN-R gene and characterise the activity of its promoter.

Characterization of calmodulin binding to the orphan nuclear receptor Errgamma.

The estrogen receptor-related receptor gamma (ERRgamma/ ERR3/NR3B3), a member of the nuclear receptor superfamily, activates transcription in the absence of ligands. In order to identify ligand-independent mechanisms of activation, we tested whether calmodulin (CaM), a key regulator of numerous cellular processes and a predominant intracellular receptor for Ca2+-signals, interacts with ERRgamma. In vitro pull-down experiments with calmodulin-Sepharose demonstrated a Ca2+-dependent interaction with cellularly expressed ERRgamma.

The germ cell nuclear factor is required for retinoic acid signaling during Xenopus development.

The germ cell nuclear factor (GCNF, NR6A1) is a nuclear orphan receptor that functions as a transcriptional repressor and is transiently expressed in mammalian carcinoma cells during retinoic acid (RA) induced neuronal differentiation. During Xenopus laevis development, the spatiotemporal expression pattern of embryonic GCNF (xEmGCNF) suggests a role in anteroposterior specification of the neuroectoderm. Here, we show that RA treatment of Xenopus embryos enhances xEmGCNF expression.

PGC-1 and PERC, coactivators of the estrogen receptor-related receptor gamma.

The mouse nuclear receptor ERRgamma (estrogen receptor-related receptor gamma) is highly expressed in heart, skeletal muscle, kidney, and brain, as well as in the developing nervous system. We found that the expression of the coactivators PGC-1 (PGC-1alpha) and PERC (PGC-1beta) in mammalian cells augmented potently the transcriptional activation by ERRgamma. The constitutive activation function 2 (AF-2) of the orphan receptor was important for the synergistic enhancement.

Domains of ERRgamma that mediate homodimerization and interaction with factors stimulating DNA binding.

The estrogen receptor-related receptor gamma (ERRgamma/ERR3/NR3B3) is an orphan member of the nuclear receptor superfamily closely related to the estrogen receptors. To explore the DNA binding characteristics, the protein-DNA interaction was studied in electrophoretic mobility shift assays (EMSAs). In vitro translated ERRgamma binds as a homodimer to direct repeats (DR) without spacing of the nuclear receptor half-site 5'-AGGTCA-3' (DR-0), to extended half-sites, and to the inverted estrogen response element.

Genomic structure of the gene for mouse germ-cell nuclear factor (GCNF). II. Comparison with the genomic structure of the human GCNF gene.

Background: Germ-cell nuclear factor (GCNF, NR6AI) is an orphan nuclear receptor. Its expression pattern suggests it functions during embryogenesis, in the placenta and in germ-cell development. Mouse GCNF cDNA codes for a protein of 495 amino acids, whereas the four reported human cDNA variants code for proteins of 454 to 480 amino acids.

Genomic structure of the gene for mouse germ cell nuclear factor (GCNF).

Background: The germ cell nuclear factor (GCNF, also known as retinoid acid receptor-related testis-associated receptor, neuronal cell nuclear receptor or NR6A1) is an orphan receptor in the nuclear receptor superfamily found in mammals, amphibians and fish. The mouse Gcnf gene is expressed in the placenta and the developing nervous system and germ cells, and responds to retinoic acid.

Results: We have defined the intron-exon structure of the mouse Gcnf gene and found that it contains 11 exons.

Developmental expression of the estrogen receptor-related receptor gamma in the nervous system during mouse embryogenesis.

The ERR's (estrogen receptor-related receptors) are constitutive activators of the classical estrogen response element. In this report, we demonstrate that ERRgamma is highly expressed in the nervous system of the developing mouse embryo and that the adult pattern of expression of ERRgamma is, with few exceptions, established during embryogenesis. Transcripts are preferentially detected in already differentiating areas of the nervous system.

Differential expression of the estrogen receptor-related receptor gamma in the mouse brain.

To elucidate estrogen functions, the expression of the estrogen receptor-related receptor ERRgamma, a novel orphan nuclear receptor regulating transcription via estrogen responsive elements, has been localized by in situ hybridization in adult murine brain. ERRgamma transcripts were abundantly present in the isocortex, the olfactory system, cranial nerve nuclei and major parts of the coordination centers, e.g.

Alternative splicing and expression of the mouse estrogen receptor-related receptor gamma.

Estrogen receptor-related receptors (ERRs) are orphan members of the nuclear receptor superfamily, closely related to the estrogen receptor. With a PCR-based cloning strategy we have identified two cDNA isoforms from a neonatal mouse whole brain cDNA library encoding ERRgamma. We show that alternative splicing gives rise to different 5'-ends.