Inhibitory actions of the NRG-1/ErbB4 pathway in macrophages during tissue fibrosis in the heart, skin, and lung.

The neuregulin-1 (NRG-1)/receptor tyrosine-protein kinase erbB (ErbB) system is an endothelium-controlled paracrine system modulating cardiac performance and adaptation. Recent studies have indicated that NRG-1 has antifibrotic effects in the left ventricle, which were explained by direct actions on cardiac fibroblasts. However, the NRG-1/ErbB system also regulates the function of macrophages.

Macrophage infiltration and genetic landscape of undifferentiated uterine sarcomas.

Endometrial stromal tumors include translocation-associated low- and high-grade endometrial stromal sarcomas (ESS) and highly malignant undifferentiated uterine sarcomas (UUS). UUS is considered a poorly defined group of aggressive tumors and is often seen as a diagnosis of exclusion after ESS and leiomyosarcoma (LMS) have been ruled out. We performed a comprehensive analysis of gene expression, copy number variation, point mutations, and immune cell infiltrates in the largest series to date of all major types of uterine sarcomas to shed light on the biology of UUS and to identify potential novel therapeutic targets.

Erectile Dysfunction in Heme-Deficient Nitric Oxide-Unresponsive Soluble Guanylate Cyclase Knock-In Mice.

Introduction: The nitric oxide (NO), soluble guanylate cyclase (sGC), and cyclic guanosine monophosphate (cGMP) pathway is the leading pathway in penile erection.

Aim: To assess erectile function in a mouse model in which sGC is deficient in heme (apo-sGC) and unresponsive to NO.

Methods: Mutant mice (sGCβ) that express an sGC enzyme that retains basal activity but fails to respond to NO because of heme deficiency (apo-sGC) were used.

New structural insight of C-terminal region of Syntenin-1, enhancing the molecular dimerization and inhibitory function related on Syndecan-4 signaling.

The PDZ domain-containing scaffold protein, syntenin-1, binds to the transmembrane proteoglycan, syndecan-4, but the molecular mechanism/function of this interaction are unknown. Crystal structure analysis of syntenin-1/syndecan-4 cytoplasmic domains revealed that syntenin-1 forms a symmetrical pair of dimers anchored by a syndecan-4 dimer. The syndecan-4 cytoplasmic domain is a compact intertwined dimer with a symmetrical clamp shape and two antiparallel strands forming a cavity within the dimeric twist.

Ubiquitin D Regulates IRE1α/c-Jun N-terminal Kinase (JNK) Protein-dependent Apoptosis in Pancreatic Beta Cells.

Pro-inflammatory cytokines contribute to pancreatic beta cell apoptosis in type 1 diabetes at least in part by inducing endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). It remains to be determined what causes the transition from "physiological" to "apoptotic" UPR, but accumulating evidence indicates that signaling by the ER transmembrane protein IRE1α is critical for this transition. IRE1α activation is regulated by both intra-ER and cytosolic cues.

Stimulating translational research: several European life science institutions put their heads together.

Translational research leaves no-one indifferent and everyone expects a particular benefit. We as EU-LIFE (www.eu-life.

Chronic Fatigue Syndrome and DNA Hypomethylation of the Glucocorticoid Receptor Gene Promoter 1F Region: Associations With HPA Axis Hypofunction and Childhood Trauma.

Objectives: Chronic fatigue syndrome (CFS) has been associated with hypothalamic-pituitary-adrenal axis hypofunction and enhanced glucocorticoid receptor (GR) sensitivity. In addition, childhood trauma is considered a major risk factor for the syndrome. This study examines DNA methylation of the GR gene (NR3C1) in CFS and associations with childhood sexual and physical trauma.

Importance of extended protease substrate recognition motifs in steering BNIP-2 cleavage by human and mouse granzymes B.

Background: Previous screening of the substrate repertoires and substrate specificity profiles of granzymes resulted in long substrate lists highly likely containing bystander substrates. Here, a recently developed degradomics technology that allows distinguishing efficiently from less efficiently cleaved substrates was applied to study the degradome of mouse granzyme B (mGrB).

Results: In vitro kinetic degradome analysis resulted in the identification of 37 mGrB cleavage events, 9 of which could be assigned as efficiently targeted ones.

The Emerging Role of Reactive Oxygen Species Signaling during Lateral Root Development.

Overall root architecture is the combined result of primary and lateral root growth and is influenced by both intrinsic genetic programs and external signals. One of the main questions for root biologists is how plants control the number of lateral root primordia and their emergence through the main root. We recently identified S-phase kinase-associated protein2 (SKP2B) as a new early marker for lateral root development.

Role of clusters in nonclassical nucleation and growth of protein crystals.

The development of multistep nucleation theory has spurred on experimentalists to find intermediate metastable states that are relevant to the solidification pathway of the molecule under interest. A great deal of studies focused on characterizing the so-called "precritical clusters" that may arise in the precipitation process. However, in macromolecular systems, the role that these clusters might play in the nucleation process and in the second stage of the precipitation process, i.

Modules identification in protein structures: the topological and geometrical solutions.

The identification of modules in protein structures has major relevance in structural biology, with consequences in protein stability and functional classification, adding new perspectives in drug design. In this work, we present the comparison between a topological (spectral clustering) and a geometrical (k-means) approach to module identification, in the frame of a multiscale analysis of the protein architecture principles. The global consistency of an adjacency matrix based technique (spectral clustering) and a method based on full rank geometrical information (k-means) give a proof-of-concept of the relevance of protein contact networks in structure determination.

Animal models and therapeutic prospects for Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth (CMT) neuropathies are inherited neuromuscular disorders caused by a length-dependent neurodegeneration of peripheral nerves. More than 900 mutations in 60 different genes are causative of the neuropathy. Despite significant progress in therapeutic strategies, the disease remains incurable.

Reciprocal cross-regulation between RNF41 and USP8 controls cytokine receptor sorting and processing.

The mechanisms controlling the steady-state cell surface levels of cytokine receptors, and consequently the cellular response to cytokines, remain poorly understood. The number of surface-exposed receptors is a dynamic balance of de novo synthesis, transport to the plasma membrane, internalization, recycling, degradation and ectodomain shedding. We previously reported that the E3 ubiquitin ligase RING finger protein 41 (RNF41) inhibits basal lysosomal degradation and enhances ectodomain shedding of JAK2-associated cytokine receptors.

Identification of binding sites for myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 in MyD88 adapter-like (Mal).

Upon activation, Toll-like receptor 4 (TLR4) binds adapter proteins, including MyD88 (myeloid differentiation primary response gene 88) and Mal (MyD88 adapter-like) for its signal transduction. TLR4 and the adapter proteins each contain a Toll/Il-1 receptor domain (TIR domain). In this study we used random mutagenesis and the mammalian two-hybrid method MAPPIT (mammalian protein-protein interaction trap) to identify mutations in Mal that disrupt its interaction with TLR4 and/or MyD88.

N-terminal acetylation and other functions of Nα-acetyltransferases.

Protein N-terminal acetylation by Nα-acetyltransferases (NATs) is an omnipresent protein modification that affects a large number of proteins. The exact biological role of N-terminal acetylation has, however, remained enigmatic for the overall majority of affected proteins, and only for a rather small number of proteins, N-terminal acetylation was linked to various protein features including stability, localization, and interactions. This minireview tries to summarize the recent progress made in understanding the functionality of N-terminal protein acetylation and also focuses on noncanonical functions of the NATs subunits.

Identification of interaction sites for dimerization and adapter recruitment in Toll/interleukin-1 receptor (TIR) domain of Toll-like receptor 4.

Toll-like receptor signaling requires interactions of the Toll/IL-1 receptor (TIR) domains of the receptor and adapter proteins. Using the mammalian protein-protein interaction trap strategy, homology modeling, and site-directed mutagenesis, we identify the interaction surfaces in the TLR4 TIR domain for the TLR4-TLR4, TLR4-MyD88 adapter-like (MAL), and TLR4-TRIF-related adapter molecule (TRAM) interaction. Two binding sites are equally important for TLR4 dimerization and adapter recruitment.

Isolation of transcription factor complexes from Arabidopsis cell suspension cultures by tandem affinity purification.

Defining protein complexes is critical to virtually all aspects of cell biology because most cellular processes are regulated by stable or more dynamic protein interactions. Elucidation of the protein-protein interaction network around transcription factors is essential to fully understand their function and regulation. In the last decade, new technologies have emerged to study protein-protein interactions under near-physiological conditions.

Leptin receptor signaling: pathways to leptin resistance.

The identification of spontaneous mutations in the leptin- and leptin receptor (ObR)-encoding ob and db gene, respectively, opened up a new field in obesity research. Leptin, an adipocyte-derived hormone, mirrors the body's fat stores and thereby informs the brain about the body's energy status. In the hypothalamus, leptin triggers specific neuronal subpopulations, like POMC and AgRP/NPY neurons, and activates several intracellular signaling events, including the JAK/STAT, MAPK, PI3K and mTOR pathway, which eventually translates into decreased food intake and increased energy expenditure.

RNF41 (Nrdp1) controls type 1 cytokine receptor degradation and ectodomain shedding.

Cytokines, such as interferons, erythropoietin, leptin and most interleukins, signal through type 1 cytokine receptors and activate the canonical JAK-STAT pathway. Aberrant cytokine signalling underlies numerous pathologies and adequate, temporary receptor activation is therefore under tight control. Negative-feedback mechanisms are very well studied, but cellular sensitivity also depends on the number of receptors exposed at the cell surface.