Cilia-localized LKB1 regulates chemokine signaling, macrophage recruitment, and tissue homeostasis in the kidney
Polycystic kidney disease (PKD) and other renal ciliopathies are characterized by cysts, inflammation, and fibrosis. Cilia function as signaling centers, but a molecular link to inflammation in the kidney has not been established. Here, we show that cilia in renal epithelia activate chemokine signaling to recruit inflammatory cells. We identify a complex of the ciliary kinase LKB1 and several ciliopathy-related proteins including NPHP1 and PKD1. At homeostasis, this ciliary module suppresses expression of the chemokine CCL2 in tubular epithelial cells. Deletion of LKB1 or PKD1 in mouse renal tubules elevates CCL2 expressio...
Source: EMBO Journal - August 1, 2018 Category: Molecular Biology Authors: Viau, A., Bienaime, F., Lukas, K., Todkar, A. P., Knoll, M., Yakulov, T. A., Hofherr, A., Kretz, O., Helmstädter, M., Reichardt, W., Braeg, S., Aschman, T., Merkle, A., Pfeifer, D., Dumit, V. I., Gubler, M.-C., Nitschke, R., Huber, T. B., Terzi, F Tags: Cell Adhesion, Polarity & Cytoskeleton, Immunology, Molecular Biology of Disease Articles Source Type: research
RNase H2, mutated in Aicardi-Goutieres syndrome, promotes LINE-1 retrotransposition
Long INterspersed Element class 1 (LINE-1) elements are a type of abundant retrotransposons active in mammalian genomes. An average human genome contains ~100 retrotransposition-competent LINE-1s, whose activity is influenced by the combined action of cellular repressors and activators. TREX1, SAMHD1 and ADAR1 are known LINE-1 repressors and when mutated cause the autoinflammatory disorder Aicardi-Goutières syndrome (AGS). Mutations in RNase H2 are the most common cause of AGS, and its activity was proposed to similarly control LINE-1 retrotransposition. It has therefore been suggested that increased LINE-1 activity...
Source: EMBO Journal - August 1, 2018 Category: Molecular Biology Authors: Benitez-Guijarro, M., Lopez-Ruiz, C., Tarnauskaite, Z., Murina, O., Mian Mohammad, M., Williams, T. C., Fluteau, A., Sanchez, L., Vilar-Astasio, R., Garcia-Canadas, M., Cano, D., Kempen, M.-J. H., Sanchez-Pozo, A., Heras, S. R., Jackson, A. P., Reijns, M. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Immunology, Molecular Biology of Disease Articles Source Type: research
Feeding state regulates pheromone-mediated avoidance behavior via the insulin signaling pathway in Caenorhabditis elegans
Animals change sensory responses and their eventual behaviors, depending on their internal metabolic status and external food availability. However, the mechanisms underlying feeding state-dependent behavioral changes remain undefined. Previous studies have shown that Caenorhabditis elegans hermaphrodite exhibits avoidance behaviors to acute exposure of a pheromone, ascr#3 (asc-C9, C9). Here, we show that the ascr#3 avoidance behavior is modulated by feeding state via the insulin signaling pathway. Starvation increases ascr#3 avoidance behavior, and loss-of-function mutations in daf-2 insulin-like receptor gene dampen this...
Source: EMBO Journal - August 1, 2018 Category: Molecular Biology Authors: Ryu, L., Cheon, Y., Huh, Y. H., Pyo, S., Chinta, S., Choi, H., Butcher, R. A., Kim, K. Tags: Cancer, Signal Transduction, Transcription Articles Source Type: research
Cancer cells copy migratory behavior and exchange signaling networks via extracellular vesicles
Recent data showed that cancer cells from different tumor subtypes with distinct metastatic potential influence each other's metastatic behavior by exchanging biomolecules through extracellular vesicles (EVs). However, it is debated how small amounts of cargo can mediate this effect, especially in tumors where all cells are from one subtype, and only subtle molecular differences drive metastatic heterogeneity. To study this, we have characterized the content of EVs shed in vivo by two clones of melanoma (B16) tumors with distinct metastatic potential. Using the Cre-LoxP system and intravital microscopy, we show that c...
Source: EMBO Journal - August 1, 2018 Category: Molecular Biology Authors: Steenbeek, S. C., Pham, T. V., de Ligt, J., Zomer, A., Knol, J. C., Piersma, S. R., Schelfhorst, T., Huisjes, R., Schiffelers, R. M., Cuppen, E., Jimenez, C. R., van Rheenen, J. Tags: Cancer, Membrane & Intracellular Transport, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Newly produced synaptic vesicle proteins are preferentially used in synaptic transmission
Aged proteins can become hazardous to cellular function, by accumulating molecular damage. This implies that cells should preferentially rely on newly produced ones. We tested this hypothesis in cultured hippocampal neurons, focusing on synaptic transmission. We found that newly synthesized vesicle proteins were incorporated in the actively recycling pool of vesicles responsible for all neurotransmitter release during physiological activity. We observed this for the calcium sensor Synaptotagmin 1, for the neurotransmitter transporter VGAT, and for the fusion protein VAMP2 (Synaptobrevin 2). Metabolic labeling of proteins a...
Source: EMBO Journal - August 1, 2018 Category: Molecular Biology Authors: Truckenbrodt, S., Viplav, A., Jähne, S., Vogts, A., Denker, A., Wildhagen, H., Fornasiero, E. F., Rizzoli, S. O. Tags: Neuroscience Articles Source Type: research
Engrailed homeoprotein blocks degeneration in adult dopaminergic neurons through LINE-1 repression
We report that LINE-1 are expressed in substantia nigra ventral midbrain dopaminergic neurons, a class of neurons that degenerate in Parkinson's disease. In Engrailed-1 heterozygotes, these neurons show a progressive degeneration that starts at 6 weeks of age, coinciding with an increase in LINE-1 expression. Similarly, DNA damage and cell death, induced by an acute oxidative stress applied to embryonic midbrain neurons in culture or to adult midbrain dopaminergic neurons in vivo, are accompanied by enhanced LINE-1 expression. Reduction of LINE-1 activity through (i) direct transcriptional repression by Engrailed...
Source: EMBO Journal - August 1, 2018 Category: Molecular Biology Authors: Blaudin de The, F.-X., Rekaik, H., Peze-Heidsieck, E., Massiani-Beaudoin, O., Joshi, R. L., Fuchs, J., Prochiantz, A. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Neuroscience Articles Source Type: research
The replicative helicase MCM recruits cohesin acetyltransferase ESCO2 to mediate centromeric sister chromatid cohesion
Chromosome segregation depends on sister chromatid cohesion which is established by cohesin during DNA replication. Cohesive cohesin complexes become acetylated to prevent their precocious release by WAPL before cells have reached mitosis. To obtain insight into how DNA replication, cohesion establishment and cohesin acetylation are coordinated, we analysed the interaction partners of 55 human proteins implicated in these processes by mass spectrometry. This proteomic screen revealed that on chromatin the cohesin acetyltransferase ESCO2 associates with the MCM2-7 subcomplex of the replicative Cdc45-MCM-GINS helicase. The a...
Source: EMBO Journal - August 1, 2018 Category: Molecular Biology Authors: Ivanov, M. P., Ladurner, R., Poser, I., Beveridge, R., Rampler, E., Hudecz, O., Novatchkova, M., Heriche, J.-K., Wutz, G., van der Lelij, P., Kreidl, E., Hutchins, J. R., Axelsson-Ekker, H., Ellenberg, J., Hyman, A. A., Mechtler, K., Peters, J.-M. Tags: Cell Cycle, Chromatin, Epigenetics, Genomics & Functional Genomics, DNA Replication, Repair & Recombination Articles Source Type: research
Zeb1 potentiates genome-wide gene transcription with Lef1 to promote glioblastoma cell invasion
Glioblastoma is the most common and aggressive brain tumor, with a subpopulation of stem-like cells thought to mediate its recurring behavior and therapeutic resistance. The epithelial–mesenchymal transition (EMT) inducing factor Zeb1 was linked to tumor initiation, invasion, and resistance to therapy in glioblastoma, but how Zeb1 functions at molecular level and what genes it regulates remain poorly understood. Contrary to the common view that EMT factors act as transcriptional repressors, here we show that genome-wide binding of Zeb1 associates with both activation and repression of gene expression in glioblastoma ...
Source: EMBO Journal - August 1, 2018 Category: Molecular Biology Authors: Rosmaninho, P., Mükusch, S., Piscopo, V., Teixeira, V., Raposo, A. A., Warta, R., Bennewitz, R., Tang, Y., Herold-Mende, C., Stifani, S., Momma, S., Castro, D. S. Tags: Cancer, Signal Transduction, Transcription Articles Source Type: research
Reorganization of inter-chromosomal interactions in the 2q37-deletion syndrome
Chromosomes occupy distinct interphase territories in the three-dimensional nucleus. However, how these chromosome territories are arranged relative to one another is poorly understood. Here, we investigated the inter-chromosomal interactions between chromosomes 2q, 12, and 17 in human mesenchymal stem cells (MSCs) and MSC-derived cell types by DNA-FISH. We compared our findings in normal karyotypes with a three-generation family harboring a 2q37-deletion syndrome, featuring a heterozygous partial deletion of histone deacetylase 4 (HDAC4) on chr2q37. In normal karyotypes, we detected stable, recurring arrangements and inte...
Source: EMBO Journal - August 1, 2018 Category: Molecular Biology Authors: Maass, P. G., Weise, A., Rittscher, K., Lichtenwald, J., Barutcu, A. R., Liehr, T., Aydin, A., Wefeld-Neuenfeld, Y., Pölsler, L., Tinschert, S., Rinn, J. L., Luft, F. C., Bähring, S. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Molecular Biology of Disease Articles Source Type: research
The virtuous self-tolerance of virtual memory T cells
"Virtual" memory CD8+ T cells are a subset of immune cells produced by homeostatic mechanisms involving response to self-antigens, raising the possibility that these cells could mediate autoimmunity. New work by Drobek et al demonstrates that virtual memory T cells are indeed favored by stronger T-cell receptor signals but exhibit minimal autoreactivity while maintaining self-tolerance. (Source: EMBO Journal)
Source: EMBO Journal - July 13, 2018 Category: Molecular Biology Authors: Truckenbrod, E. N., Jameson, S. C. Tags: Immunology News [amp ] Views Source Type: research
Periodic fasting starves cisplatin-resistant cancers to death
Treatment of cancers with the cytotoxic agent cisplatin frequently evokes resistance, accompanied by rewiring of metabolic pathways, limiting its clinical use. Recent research by Obrist et al (2018) shows that cisplatin-resistant growth of lung adenocarcinoma is particularly vulnerable to periodic fasting cycles and starvation-induced cell death, due to its dependency on glutamine, required for nucleoside biosynthesis, suggesting an opportunity for nutritional anti-cancer interventions. (Source: EMBO Journal)
Source: EMBO Journal - July 13, 2018 Category: Molecular Biology Authors: Guidi, N., Longo, V. D. Tags: Cancer, Autophagy & Cell Death, Metabolism News [amp ] Views Source Type: research
Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease
The failure of DNA ligases to complete their catalytic reactions generates cytotoxic adenylated DNA strand breaks. The APTX RNA-DNA deadenylase protects genome integrity and corrects abortive DNA ligation arising during ribonucleotide excision repair and base excision DNA repair, and APTX human mutations cause the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1). How APTX senses cognate DNA nicks and is inactivated in AOA1 remains incompletely defined. Here, we report X-ray structures of APTX engaging nicked RNA-DNA substrates that provide direct evidence for a wedge-pivot-cut strategy for 5'-AMP resolutio...
Source: EMBO Journal - July 13, 2018 Category: Molecular Biology Authors: Tumbale, P., Schellenberg, M. J., Mueller, G. A., Fairweather, E., Watson, M., Little, J. N., Krahn, J., Waddell, I., London, R. E., Williams, R. S. Tags: DNA Replication, Repair & Recombination, Molecular Biology of Disease, Structural Biology Articles Source Type: research
Lmo2 expression defines tumor cell identity during T-cell leukemogenesis
The impact of LMO2 expression on cell lineage decisions during T-cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T-cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human-like T-ALL. In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction ...
Source: EMBO Journal - July 13, 2018 Category: Molecular Biology Authors: Garcia-Ramirez, I., Bhatia, S., Rodriguez-Hernandez, G., Gonzalez-Herrero, I., Walter, C., Gonzalez de Tena-Davila, S., Parvin, S., Haas, O., Woessmann, W., Stanulla, M., Schrappe, M., Dugas, M., Natkunam, Y., Orfao, A., Dominguez, V., Pintado, B., Blanco Tags: Cancer, Development & Differentiation, Immunology Articles Source Type: research
Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1{alpha}
Family with sequence similarity 20C (Fam20C), the physiological Golgi casein kinase, phosphorylates numerous secreted proteins that are involved in a wide variety of biological processes. However, the role of Fam20C in regulating proteins in the endoplasmic reticulum (ER) lumen is largely unknown. Here, we report that Fam20C interacts with various luminal proteins and that its depletion results in a more reduced ER lumen. We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde...
Source: EMBO Journal - July 13, 2018 Category: Molecular Biology Authors: Zhang, J., Zhu, Q., Wang, X., Yu, J., Chen, X., Wang, J., Wang, X., Xiao, J., Wang, C.-c., Wang, L. Tags: Membrane & Intracellular Transport, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Metabolic vulnerability of cisplatin-resistant cancers
Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant poses a major problem in clinical oncology. Here, we explored potential metabolic vulnerabilities of cisplatin-resistant non-small human cell lung cancer and ovarian cancer cell lines. Cisplatin-resistant clones were more sensitive to killing by nutrient deprivation in vitro and in vivo than their parental cisplatin-sensitive controls. The susceptibility of cisplatin-resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient...
Source: EMBO Journal - July 13, 2018 Category: Molecular Biology Authors: Obrist, F., Michels, J., Durand, S., Chery, A., Pol, J., Levesque, S., Joseph, A., Astesana, V., Pietrocola, F., Wu, G. S., Castedo, M., Kroemer, G. Tags: Cancer, Autophagy & Cell Death, Metabolism Articles Source Type: research
