Tumor suppressor PNRC1 blocks rRNA maturation by recruiting the decapping complex to the nucleolus
Focal deletions occur frequently in the cancer genome. However, the putative tumor-suppressive genes residing within these regions have been difficult to pinpoint. To robustly identify these genes, we implemented a computational approach based on non-negative matrix factorization, NMF, and interrogated the TCGA dataset. This analysis revealed a metagene signature including a small subset of genes showing pervasive hemizygous deletions, reduced expression in cancer patient samples, and nucleolar function. Amid the genes belonging to this signature, we have identified PNRC1, a nuclear receptor coactivator. We found that PNRC...
Source: EMBO Journal - December 3, 2018 Category: Molecular Biology Authors: Gaviraghi, M., Vivori, C., Pareja Sanchez, Y., Invernizzi, F., Cattaneo, A., Santoliquido, B. M., Frenquelli, M., Segalla, S., Bachi, A., Doglioni, C., Pelechano, V., Cittaro, D., Tonon, G. Tags: Cancer, RNA Biology Articles Source Type: research
Function of HNRNPC in breast cancer cells by controlling the dsRNA-induced interferon response
Elevated expression of RNA binding protein HNRNPC has been reported in cancer cells, while the essentialness and functions of HNRNPC in tumors were not clear. We showed that repression of HNRNPC in the breast cancer cells MCF7 and T47D inhibited cell proliferation and tumor growth. Our computational inference of the key pathways and extensive experimental investigations revealed that the cascade of interferon responses mediated by RIG-I was responsible for such tumor-inhibitory effect. Interestingly, repression of HNRNPC resulted in accumulation of endogenous double-stranded RNA (dsRNA), the binding ligand of RIG-I. These ...
Source: EMBO Journal - December 3, 2018 Category: Molecular Biology Authors: Wu, Y., Zhao, W., Liu, Y., Tan, X., Li, X., Zou, Q., Xiao, Z., Xu, H., Wang, Y., Yang, X. Tags: Cancer, Immunology Articles Source Type: research
Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma
Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast-cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow-cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCCs display enhanced invasion and chemoresistance, suggesting their import...
Source: EMBO Journal - December 3, 2018 Category: Molecular Biology Authors: Hoang-Minh, L. B., Siebzehnrubl, F. A., Yang, C., Suzuki-Hatano, S., Dajac, K., Loche, T., Andrews, N., Schmoll Massari, M., Patel, J., Amin, K., Vuong, A., Jimenez-Pascual, A., Kubilis, P., Garrett, T. J., Moneypenny, C., Pacak, C. A., Huang, J., Sayour, Tags: Cancer, Metabolism, Stem Cells Articles Source Type: research
Stress-induced host membrane remodeling protects from infection by non-motile bacterial pathogens
While mucosal inflammation is a major source of stress during enteropathogen infection, it remains to be fully elucidated how the host benefits from this environment to clear the pathogen. Here, we show that host stress induced by different stimuli mimicking inflammatory conditions strongly reduces the binding of Shigella flexneri to epithelial cells. Mechanistically, stress activates acid sphingomyelinase leading to host membrane remodeling. Consequently, knockdown or pharmacological inhibition of the acid sphingomyelinase blunts the stress-dependent inhibition of Shigella binding to host cells. Interestingly, stress caus...
Source: EMBO Journal - December 3, 2018 Category: Molecular Biology Authors: Tawk, C., Nigro, G., Rodrigues Lopes, I., Aguilar, C., Lisowski, C., Mano, M., Sansonetti, P., Vogel, J., Eulalio, A. Tags: Membrane & Intracellular Transport, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
Putting a strain on diversity
Human life expectancy is increasing on a global scale, but healthspan—the period of life free from age-associated ill health—is not improving at a comparable rate. This disconnect means that a greater proportion of the general population will spend a longer period of their life suffering from one or more debilitating age-associated diseases, such as cardiovascular disease, Alzheimer's disease, osteoporosis, sarcopenia and various cancers. Understanding the processes underlying ageing and age-related diseases is therefore a major and pressing research challenge in biomedical research. (Source: EMBO Journal)
Source: EMBO Journal - November 15, 2018 Category: Molecular Biology Authors: Selman, C., Swindell, W. R. Tags: Ageing, Genetics, Gene Therapy & Genetic Disease Commentary Source Type: research
Are you TORCing tau me? Amyloid-{beta} blocks the conversation between lysosomes and mitochondria
How amyloid-β (Aβ) and tau exacerbate Alzheimer's disease (AD) at a subcellular level is only incompletely understood. Norambuena et al (2018) report crosstalk between mitochondria and lysosomes and identify a role for lysosomal mTORC1 in the nutrient-induced activation of mitochondria. This lysosomal signalling pathway is strongly inhibited by oligomeric Aβ through the tau-dependent activation of plasma membrane-localized mTORC1. Together, these results identify a further role for tau in mediating Aβ toxicity. (Source: EMBO Journal)
Source: EMBO Journal - November 15, 2018 Category: Molecular Biology Authors: Polanco, J. C., Götz, J. Tags: Autophagy & Cell Death, Metabolism, Neuroscience News [amp ] Views Source Type: research
Hepatic ERAD takes control of the organism
Upregulation of Endoplasmic Reticulum-Associated Degradation (ERAD) in the liver upon feeding and organismal growth aggravates proteasomal turnover of the transcription factor CREBH and decreases the expression of its target gene, the hepatokine FGF21. Wei et al and Bhattacharya et al describe the systemic coordination of energy metabolism and organismal physiology mediated by hepatic-specific ERAD function. (Source: EMBO Journal)
Source: EMBO Journal - November 15, 2018 Category: Molecular Biology Authors: Dreher, L.-S., Hoppe, T. Tags: Membrane & Intracellular Transport, Metabolism, Post-translational Modifications, Proteolysis & Proteomics News [amp ] Views Source Type: research
Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth
The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap–/– mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis. Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap–/– mutants, and impaire...
Source: EMBO Journal - November 15, 2018 Category: Molecular Biology Authors: Cox, A. G., Tsomides, A., Yimlamai, D., Hwang, K. L., Miesfeld, J., Galli, G. G., Fowl, B. H., Fort, M., Ma, K. Y., Sullivan, M. R., Hosios, A. M., Snay, E., Yuan, M., Brown, K. K., Lien, E. C., Chhangawala, S., Steinhauser, M. L., Asara, J. M., Houvras, Tags: Development & Differentiation, Metabolism Articles Source Type: research
A novel lysosome-to-mitochondria signaling pathway disrupted by amyloid-{beta} oligomers
The mechanisms of mitochondrial dysfunction in Alzheimer's disease are incompletely understood. Using two-photon fluorescence lifetime microscopy of the coenzymes, NADH and NADPH, and tracking brain oxygen metabolism with multi-parametric photoacoustic microscopy, we show that activation of lysosomal mechanistic target of rapamycin complex 1 (mTORC1) by insulin or amino acids stimulates mitochondrial activity and regulates mitochondrial DNA synthesis in neurons. Amyloid-β oligomers, which are precursors of amyloid plaques in Alzheimer's disease brain and stimulate mTORC1 protein kinase activity at the plasma membrane ...
Source: EMBO Journal - November 15, 2018 Category: Molecular Biology Authors: Norambuena, A., Wallrabe, H., Cao, R., Wang, D. B., Silva, A., Svindrych, Z., Periasamy, A., Hu, S., Tanzi, R. E., Kim, D. Y., Bloom, G. S. Tags: Autophagy & Cell Death, Metabolism, Neuroscience Articles Source Type: research
Structure of the nucleation-promoting factor SPIN90 bound to the actin filament nucleator Arp2/3 complex
Unlike the WASP family of Arp2/3 complex activators, WISH/DIP/SPIN90 (WDS) family proteins activate actin filament nucleation by the Arp2/3 complex without the need for a preformed actin filament. This allows WDS proteins to initiate branched actin network assembly by providing seed filaments that activate WASP-bound Arp2/3 complex. Despite their important role in actin network initiation, it is unclear how WDS proteins drive the activating steps that require both WASP and pre-existing actin filaments during WASP-mediated nucleation. Here, we show that SPIN90 folds into an armadillo repeat domain that binds a surface of Ar...
Source: EMBO Journal - November 15, 2018 Category: Molecular Biology Authors: Luan, Q., Liu, S.-L., Helgeson, L. A., Nolen, B. J. Tags: Cell Adhesion, Polarity & Cytoskeleton, Structural Biology Articles Source Type: research
Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH
This study not only establishes the importance of Sel1L-Hrd1 ERAD in the liver in the regulation of systemic energy metabolism, but also reveals a novel hepatic "ERAD-Crebh-Fgf21" axis directly linking ER protein turnover to gene transcription and systemic metabolic regulation. (Source: EMBO Journal)
Source: EMBO Journal - November 15, 2018 Category: Molecular Biology Authors: Bhattacharya, A., Sun, S., Wang, H., Liu, M., Long, Q., Yin, L., Kersten, S., Zhang, K., Qi, L. Tags: Membrane & Intracellular Transport, Metabolism, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Local activation of mammalian separase in interphase promotes double-strand break repair and prevents oncogenic transformation
Separase halves eukaryotic chromosomes in M-phase by cleaving cohesin complexes holding sister chromatids together. Whether this essential protease functions also in interphase and/or impacts carcinogenesis remains largely unknown. Here, we show that mammalian separase is recruited to DNA double-strand breaks (DSBs) where it is activated to locally cleave cohesin and facilitate homology-directed repair (HDR). Inactivating phosphorylation of its NES, arginine methylation of its RG-repeats, and sumoylation redirect separase from the cytosol to DSBs. In vitro assays suggest that DNA damage response-relevant ATM, PRMT1, and Mm...
Source: EMBO Journal - November 15, 2018 Category: Molecular Biology Authors: Hellmuth, S., Gutierrez-Caballero, C., Llano, E., Pendas, A. M., Stemmann, O. Tags: Cell Cycle, DNA Replication, Repair & Recombination, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity
Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others activates G protein-coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector, which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD...
Source: EMBO Journal - November 15, 2018 Category: Molecular Biology Authors: Löffler, M. C., Mayer, A. E., Trujillo Viera, J., Loza Valdes, A., El-Merahbi, R., Ade, C. P., Karwen, T., Schmitz, W., Slotta, A., Erk, M., Janaki-Raman, S., Matesanz, N., Torres, J. L., Marcos, M., Sabio, G., Eilers, M., Schulze, A., Sumara, G. Tags: Development & Differentiation, Metabolism Articles Source Type: research
HRD1-ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination
The endoplasmic reticulum-associated protein degradation (ERAD) is responsible for recognizing and retro-translocating protein substrates, misfolded or not, from the ER for cytosolic proteasomal degradation. HMG-CoA Reductase (HMGCR) Degradation protein—HRD1—was initially identified as an E3 ligase critical for ERAD. However, its physiological functions remain largely undefined. Herein, we discovered that hepatic HRD1 expression is induced in the postprandial condition upon mouse refeeding. Mice with liver-specific HRD1 deletion failed to repress FGF21 production in serum and liver even in the refeeding conditi...
Source: EMBO Journal - November 15, 2018 Category: Molecular Biology Authors: Wei, J., Chen, L., Li, F., Yuan, Y., Wang, Y., Xia, W., Zhang, Y., Xu, Y., Yang, Z., Gao, B., Jin, C., Melo-Cardenas, J., Green, R. M., Pan, H., Wang, J., He, F., Zhang, K., Fang, D. Tags: Membrane & Intracellular Transport, Metabolism, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Distinct roles of VE-cadherin for development and maintenance of specific lymph vessel beds
Endothelial cells line blood and lymphatic vessels and form intercellular junctions, which preserve vessel structure and integrity. The vascular endothelial cadherin, VE-cadherin, mediates endothelial adhesion and is indispensible for blood vessel development and permeability regulation. However, its requirement for lymphatic vessels has not been addressed. During development, VE-cadherin deletion in lymphatic endothelial cells resulted in abortive lymphangiogenesis, edema, and prenatal death. Unexpectedly, inducible postnatal or adult deletion elicited vessel bed-specific responses. Mature dermal lymph vessels resisted VE...
Source: EMBO Journal - November 15, 2018 Category: Molecular Biology Authors: Hägerling, R., Hoppe, E., Dierkes, C., Stehling, M., Makinen, T., Butz, S., Vestweber, D., Kiefer, F. Tags: Cell Adhesion, Polarity & Cytoskeleton, Development & Differentiation, Vascular Biology & Angiogenesis Articles Source Type: research
