Ubiquitin-specific protease USP34 controls osteogenic differentiation and bone formation by regulating BMP2 signaling
The osteogenic differentiation of mesenchymal stem cells (MSCs) is governed by multiple mechanisms. Growing evidence indicates that ubiquitin-dependent protein degradation is critical for the differentiation of MSCs and bone formation; however, the function of ubiquitin-specific proteases, the largest subfamily of deubiquitylases, remains unclear. Here, we identify USP34 as a previously unknown regulator of osteogenesis. The expression of USP34 in human MSCs increases after osteogenic induction while depletion of USP34 inhibits osteogenic differentiation. Conditional knockout of Usp34 from MSCs or pre-osteoblasts leads to ...
Source: EMBO Journal - October 15, 2018 Category: Molecular Biology Authors: Guo, Y.-c., Wang, M.-y., Zhang, S.-w., Wu, Y.-s., Zhou, C.-c., Zheng, R.-x., Shao, B., Wang, Y., Xie, L., Liu, W.-q., Sun, N.-y., Jing, J.-j., Ye, L., Chen, Q.-m., Yuan, Q. Tags: Development & Differentiation, Post-translational Modifications, Proteolysis & Proteomics, Signal Transduction Articles Source Type: research
CDK1-mediated BCL9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling
Uncontrolled cell division is a hallmark of cancer. Deregulation of Wnt components has been linked to aberrant cell division by multiple mechanisms, including Wnt-mediated stabilisation of proteins signalling, which was notably observed in mitosis. Analysis of Wnt components revealed an unexpected role of B-cell CLL/lymphoma 9 (BCL9) in maintaining mitotic Wnt signalling to promote precise cell division and growth of cancer cell. Mitotic interactome analysis revealed a mechanistic role of BCL9 in inhibiting clathrin-mediated degradation of LRP6 signalosome components by interacting with clathrin and the components in Wnt d...
Source: EMBO Journal - October 15, 2018 Category: Molecular Biology Authors: Chen, J., Rajasekaran, M., Xia, H., Kong, S. N., Deivasigamani, A., Sekar, K., Gao, H., Swa, H. L., Gunaratne, J., Ooi, L. L., Xie, T., Hong, W., Hui, K. M. Tags: Cancer, Cell Cycle, Signal Transduction Articles Source Type: research
Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction
Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endo...
Source: EMBO Journal - October 15, 2018 Category: Molecular Biology Authors: Vaz-Silva, J., Gomes, P., Jin, Q., Zhu, M., Zhuravleva, V., Quintremil, S., Meira, T., Silva, J., Dioli, C., Soares-Cunha, C., Daskalakis, N. P., Sousa, N., Sotiropoulos, I., Waites, C. L. Tags: Membrane & Intracellular Transport, Neuroscience Articles Source Type: research
CPEB2-dependent translation of long 3'-UTR Ucp1 mRNA promotes thermogenesis in brown adipose tissue
Expression of mitochondrial proton transporter uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is essential for mammalian thermogenesis. While human UCP1 mRNA exists in a long form only, alternative polyadenylation creates two different isoforms in mice with 10% of UCP1 mRNA found in the long form (Ucp1L) and ~90% in the short form (Ucp1S). We generated a mouse model expressing only Ucp1S and found that it showed impaired thermogenesis due to a 60% drop in UCP1 protein levels, suggesting that Ucp1L is more efficiently translated than Ucp1S. In addition, we found that β3 adrenergic receptor signaling promoted...
Source: EMBO Journal - October 15, 2018 Category: Molecular Biology Authors: Chen, H.-F., Hsu, C.-M., Huang, Y.-S. Tags: Metabolism, Protein Biosynthesis & Quality Control, RNA Biology Articles Source Type: research
Epigenetic reprogramming by histone acetyltransferase HAG1/AtGCN5 is required for pluripotency acquisition in Arabidopsis
Shoot regeneration can be achieved in vitro through a two-step process involving the acquisition of pluripotency on callus-induction media (CIM) and the formation of shoots on shoot-induction media. Although the induction of root-meristem genes in callus has been noted recently, the mechanisms underlying their induction and their roles in de novo shoot regeneration remain unanswered. Here, we show that the histone acetyltransferase HAG1/AtGCN5 is essential for de novo shoot regeneration. In developing callus, it catalyzes histone acetylation at several root-meristem gene loci including WOX5, WOX14, SCR, PLT1, and PLT2...
Source: EMBO Journal - October 15, 2018 Category: Molecular Biology Authors: Kim, J.-Y., Yang, W., Forner, J., Lohmann, J. U., Noh, B., Noh, Y.-S. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Development & Differentiation, Plant Biology Articles Source Type: research
Uncovering the "secret" lives of vacuolar fusion pores in living cells
Non-expanding fusion pores have been predicted to constitute rate-limiting metastable intermediates in a broad range of fusion processes ranging from exocytosis to cell–cell fusion. However, their existence and nature, in particular in intracellular non-exocytic compartments, remained largely intangible. In this issue, D'Agostino et al demonstrate that non-expanding pores are likely long-lived steady-state intermediates in yeast vacuoles allowing the cells to adjust their volume to rapidly changing physiology. These pores are stabilized against closure by SNAREs and the attached vacuolar vesicle tethering comple...
Source: EMBO Journal - October 1, 2018 Category: Molecular Biology Authors: Söllner, T. H., Malsam, J. Tags: Membrane & Intracellular Transport News [amp ] Views Source Type: research
Buried in PEAT--discovery of a new silencing complex with opposing activities
Posttranslational histone modifications serve critical roles in gene regulation by determining the functional status of chromatin. Histone-modifying enzymes often work in large multiprotein complexes. A paper in this issue of The EMBO Journal describes a new chromatin-modifying complex called PEAT that acts via histone deacetylation. The PEAT complex is involved in heterochromatin formation and gene repression but also appears to have a locus-specific activating role, possibly through promoting histone acetylation. (Source: EMBO Journal)
Source: EMBO Journal - October 1, 2018 Category: Molecular Biology Authors: Tsuzuki, M., Wierzbicki, A. T. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Plant Biology, RNA Biology News [amp ] Views Source Type: research
SNARE-mediated membrane fusion arrests at pore expansion to regulate the volume of an organelle
Constitutive membrane fusion within eukaryotic cells is thought to be controlled at its initial steps, membrane tethering and SNARE complex assembly, and to rapidly proceed from there to full fusion. Although theory predicts that fusion pore expansion faces a major energy barrier and might hence be a rate-limiting and regulated step, corresponding states with non-expanding pores are difficult to assay and have remained elusive. Here, we show that vacuoles in living yeast are connected by a metastable, non-expanding, nanoscopic fusion pore. This is their default state, from which full fusion is regulated. Molecular dynamics...
Source: EMBO Journal - October 1, 2018 Category: Molecular Biology Authors: D'Agostino, M., Risselada, H. J., Endter, L. J., Comte-Miserez, V., Mayer, A. Tags: Membrane & Intracellular Transport Articles Source Type: research
SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F
We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation. (Source: EMBO Journal)
Source: EMBO Journal - October 1, 2018 Category: Molecular Biology Authors: Ayhan, F., Perez, B. A., Shorrock, H. K., Zu, T., Banez-Coronel, M., Reid, T., Furuya, H., Clark, H. B., Troncoso, J. C., Ross, C. A., Subramony, S., Ashizawa, T., Wang, E. T., Yachnis, A. T., Ranum, L. P. Tags: Molecular Biology of Disease, Neuroscience Articles Source Type: research
Histone H2A-H2B binding by Pol {alpha} in the eukaryotic replisome contributes to the maintenance of repressive chromatin
The eukaryotic replisome disassembles parental chromatin at DNA replication forks, but then plays a poorly understood role in the re-deposition of the displaced histone complexes onto nascent DNA. Here, we show that yeast DNA polymerase α contains a histone-binding motif that is conserved in human Pol α and is specific for histones H2A and H2B. Mutation of this motif in budding yeast cells does not affect DNA synthesis, but instead abrogates gene silencing at telomeres and mating-type loci. Similar phenotypes are produced not only by mutations that displace Pol α from the replisome, but also by mutation o...
Source: EMBO Journal - October 1, 2018 Category: Molecular Biology Authors: Evrin, C., Maman, J. D., Diamante, A., Pellegrini, L., Labib, K. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, DNA Replication, Repair & Recombination Articles Source Type: research
Molecular dissection of plasmacytoid dendritic cell activation in vivo during a viral infection
Plasmacytoid dendritic cells (pDC) are the major source of type I interferons (IFN-I) during viral infections, in response to triggering of endosomal Toll-like receptors (TLRs) 7 or 9 by viral single-stranded RNA or unmethylated CpG DNA, respectively. Synthetic ligands have been used to disentangle the underlying signaling pathways. The adaptor protein AP3 is necessary to transport molecular complexes of TLRs, synthetic CpG DNA, and MyD88 into endosomal compartments allowing interferon regulatory factor 7 (IRF7) recruitment whose phosphorylation then initiates IFN-I production. High basal expression of IRF7 by pDC and its ...
Source: EMBO Journal - October 1, 2018 Category: Molecular Biology Authors: Tomasello, E., Naciri, K., Chelbi, R., Bessou, G., Fries, A., Gressier, E., Abbas, A., Pollet, E., Pierre, P., Lawrence, T., Vu Manh, T.-P., Dalod, M. Tags: Immunology, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
The PEAT protein complexes are required for histone deacetylation and heterochromatin silencing
In eukaryotes, heterochromatin regions are typically subjected to transcriptional silencing. DNA methylation has an important role in such silencing and has been studied extensively. However, little is known about how methylated heterochromatin regions are subjected to silencing. We conducted a genetic screen and identified an epcr (enhancer of polycomb-related) mutant that releases heterochromatin silencing in Arabidopsis thaliana. We demonstrated that EPCR1 functions redundantly with its paralog EPCR2 and interacts with PWWP domain-containing proteins (PWWPs), AT-rich interaction domain-containing proteins (ARIDs), and t...
Source: EMBO Journal - October 1, 2018 Category: Molecular Biology Authors: Tan, L.-M., Zhang, C.-J., Hou, X.-M., Shao, C.-R., Lu, Y.-J., Zhou, J.-X., Li, Y.-Q., Li, L., Chen, S., He, X.-J. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, RNA Biology Articles Source Type: research
Evidence for the nuclear import of histones H3.1 and H4 as monomers
Newly synthesised histones are thought to dimerise in the cytosol and undergo nuclear import in complex with histone chaperones. Here, we provide evidence that human H3.1 and H4 are imported into the nucleus as monomers. Using a tether-and-release system to study the import dynamics of newly synthesised histones, we find that cytosolic H3.1 and H4 can be maintained as stable monomeric units. Cytosolically tethered histones are bound to importin-alpha proteins (predominantly IPO4), but not to histone-specific chaperones NASP, ASF1a, RbAp46 (RBBP7) or HAT1, which reside in the nucleus in interphase cells. Release of monomeri...
Source: EMBO Journal - October 1, 2018 Category: Molecular Biology Authors: Apta-Smith, M. J., Hernandez-Fernaud, J. R., Bowman, A. J. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Membrane & Intracellular Transport, Protein Biosynthesis & Quality Control Articles Source Type: research
Arabidopsis O-GlcNAc transferase SEC activates histone methyltransferase ATX1 to regulate flowering
Post-translational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) is catalyzed by O-GlcNAc transferases (OGTs). O-GlcNAc modification of proteins regulates multiple important biological processes in metazoans. However, whether protein O-GlcNAcylation is involved in epigenetic processes during plant development is largely unknown. Here, we show that loss of function of SECRET AGENT (SEC), an OGT in Arabidopsis, leads to an early flowering phenotype. This results from reduced histone H3 lysine 4 trimethylation (H3K4me3) of FLOWERING LOCUS C (FLC) locus, which encodes a key negative regulator of fl...
Source: EMBO Journal - October 1, 2018 Category: Molecular Biology Authors: Xing, L., Liu, Y., Xu, S., Xiao, J., Wang, B., Deng, H., Lu, Z., Xu, Y., Chong, K. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Plant Biology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Lipase maturation factor 1 affects redox homeostasis in the endoplasmic reticulum
Lipoprotein lipase (LPL) is a secreted lipase that clears triglycerides from the blood. Proper LPL folding and exit from the endoplasmic reticulum (ER) require lipase maturation factor 1 (LMF1), an ER-resident transmembrane protein, but the mechanism involved is unknown. We used proteomics to identify LMF1-binding partners necessary for LPL secretion in HEK293 cells and found these to include oxidoreductases and lectin chaperones, suggesting that LMF1 facilitates the formation of LPL's five disulfide bonds. In accordance with this role, we found that LPL aggregates in LMF1-deficient cells due to the formation of incorrect ...
Source: EMBO Journal - October 1, 2018 Category: Molecular Biology Authors: Roberts, B. S., Babilonia-Rosa, M. A., Broadwell, L. J., Wu, M. J., Neher, S. B. Tags: Protein Biosynthesis & Quality Control Articles Source Type: research
