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https://www.readbyqxmd.com/read/29158324/control-of-rab7-activity-and-localization-through-the-retromer-tbc1d5-complex-enables-rab7-dependent-mitophagy
#1
Ana Jimenez-Orgaz, Arunas Kvainickas, Heike Nägele, Justin Denner, Stefan Eimer, Jörn Dengjel, Florian Steinberg
Retromer is an endosomal multi-protein complex that organizes the endocytic recycling of a vast range of integral membrane proteins. Here, we establish an additional retromer function in controlling the activity and localization of the late endosomal small GTPase RAB7. Surprisingly, we found that RAB7 not only decorates late endosomes or lysosomes, but is also present on the endoplasmic reticulum, trans-Golgi network, and mitochondrial membranes, a localization that is maintained by retromer and the retromer-associated RAB7-specific GAP TBC1D5...
November 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29150433/tyrosine-phosphorylation-of-munc18-1-inhibits-synaptic-transmission-by-preventing-snare%C3%A2-assembly
#2
Marieke Meijer, Bernhard Dörr, Hanna Ca Lammertse, Chrysanthi Blithikioti, Jan Rt van Weering, Ruud Fg Toonen, Thomas H Söllner, Matthijs Verhage
Tyrosine kinases are important regulators of synaptic strength. Here, we describe a key component of the synaptic vesicle release machinery, Munc18-1, as a phosphorylation target for neuronal Src family kinases (SFKs). Phosphomimetic Y473D mutation of a SFK phosphorylation site previously identified by brain phospho-proteomics abolished the stimulatory effect of Munc18-1 on SNARE complex formation ("SNARE-templating") and membrane fusion in vitro Furthermore, priming but not docking of synaptic vesicles was disrupted in hippocampal munc18-1-null neurons expressing Munc18-1Y473D Synaptic transmission was temporarily restored by high-frequency stimulation, as well as by a Munc18-1 mutation that results in helix 12 extension, a critical conformational step in vesicle priming...
November 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29150432/the-ikk-related-kinase-tbk1-activates-mtorc1-directly-in-response-to-growth-factors-and-innate-immune-agonists
#3
Cagri Bodur, Dubek Kazyken, Kezhen Huang, Bilgen Ekim Ustunel, Kate A Siroky, Aaron Seth Tooley, Ian E Gonzalez, Daniel H Foley, Hugo A Acosta-Jaquez, Tammy M Barnes, Gabrielle K Steinl, Kae-Won Cho, Carey N Lumeng, Steven M Riddle, Martin G Myers, Diane C Fingar
The innate immune kinase TBK1 initiates inflammatory responses to combat infectious pathogens by driving production of type I interferons. TBK1 also controls metabolic processes and promotes oncogene-induced cell proliferation and survival. Here, we demonstrate that TBK1 activates mTOR complex 1 (mTORC1) directly. In cultured cells, TBK1 associates with and activates mTORC1 through site-specific mTOR phosphorylation (on S2159) in response to certain growth factor receptors (i.e., EGF-receptor but not insulin receptor) and pathogen recognition receptors (PRRs) (i...
November 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29150431/the-e3-ubiquitin-ligase-apc-c-c-dh1-degrades-mcph1-after-mcph1-%C3%AE-trcp2-cdc25a-mediated-mitotic-entry-to-ensure-neurogenesis
#4
Xiaoqian Liu, Wen Zong, Tangliang Li, Yujun Wang, Xingzhi Xu, Zhong-Wei Zhou, Zhao-Qi Wang
Mutations of microcephalin (MCPH1) can cause the neurodevelopmental disorder primary microcephaly type 1. We previously showed that MCPH1 deletion in neural stem cells results in early mitotic entry that distracts cell division mode, leading to exhaustion of the progenitor pool. Here, we show that MCPH1 interacts with and promotes the E3 ligase βTrCP2 to degrade Cdc25A independent of DNA damage. Overexpression of βTrCP2 or the knockdown of Cdc25A remedies the high mitotic index and rescues the premature differentiation of Mcph1-deficient neuroprogenitors in vivo MCPH1 itself is degraded by APC/C(C)(dh1), but not APC/C(C)(dc20), in late mitosis and G1 phase...
November 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29146773/glyoxal-as-an-alternative-fixative-to-formaldehyde-in-immunostaining-and-super-resolution-microscopy
#5
Katharina N Richter, Natalia H Revelo, Katharina J Seitz, Martin S Helm, Deblina Sarkar, Rebecca S Saleeb, Elisa D'Este, Jessica Eberle, Eva Wagner, Christian Vogl, Diana F Lazaro, Frank Richter, Javier Coy-Vergara, Giovanna Coceano, Edward S Boyden, Rory R Duncan, Stefan W Hell, Marcel A Lauterbach, Stephan E Lehnart, Tobias Moser, Tiago Outeiro, Peter Rehling, Blanche Schwappach, Ilaria Testa, Bolek Zapiec, Silvio O Rizzoli
Paraformaldehyde (PFA) is the most commonly used fixative for immunostaining of cells, but has been associated with various problems, ranging from loss of antigenicity to changes in morphology during fixation. We show here that the small dialdehyde glyoxal can successfully replace PFA Despite being less toxic than PFA, and, as most aldehydes, likely usable as a fixative, glyoxal has not yet been systematically tried in modern fluorescence microscopy. Here, we tested and optimized glyoxal fixation and surprisingly found it to be more efficient than PFA-based protocols...
November 16, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29141912/wh2-and-proline-rich-domains-of-wasp-family-proteins-collaborate-to-accelerate-actin-filament-elongation
#6
Peter Bieling, Scott D Hansen, Orkun Akin, Tai-De Li, Carl C Hayden, Daniel A Fletcher, R Dyche Mullins
WASP-family proteins are known to promote assembly of branched actin networks by stimulating the filament-nucleating activity of the Arp2/3 complex. Here, we show that WASP-family proteins also function as polymerases that accelerate elongation of uncapped actin filaments. When clustered on a surface, WASP-family proteins can drive branched actin networks to grow much faster than they could by direct incorporation of soluble monomers. This polymerase activity arises from the coordinated action of two regulatory sequences: (i) a WASP homology 2 (WH2) domain that binds actin, and (ii) a proline-rich sequence that binds profilin-actin complexes...
November 15, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29133469/an-invisible-ubiquitin-conformation-is-required-for-efficient-phosphorylation-by-pink1
#7
Christina Gladkova, Alexander F Schubert, Jane L Wagstaff, Jonathan N Pruneda, Stefan M V Freund, David Komander
The Ser/Thr protein kinase PINK1 phosphorylates the well-folded, globular protein ubiquitin (Ub) at a relatively protected site, Ser65. We previously showed that Ser65 phosphorylation results in a conformational change in which Ub adopts a dynamic equilibrium between the known, common Ub conformation and a distinct, second conformation wherein the last β-strand is retracted to extend the Ser65 loop and shorten the C-terminal tail. We show using chemical exchange saturation transfer (CEST) nuclear magnetic resonance experiments that a similar, C-terminally retracted (Ub-CR) conformation also exists at low population in wild-type Ub...
November 13, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29127156/myc-and-tumor-metabolism-chicken-and-egg
#8
REVIEW
Francesca R Dejure, Martin Eilers
Transcription factors of the MYC family are deregulated in the majority of all human cancers. Oncogenic levels of MYC reprogram cellular metabolism, a hallmark of cancer development, to sustain the high rate of proliferation of cancer cells. Conversely, cells need to modulate MYC function according to the availability of nutrients, in order to avoid a metabolic collapse. Here, we review recent evidence that the multiple interactions of MYC with cell metabolism are mutual and review mechanisms that control MYC levels and function in response to metabolic stress situations...
November 10, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29127155/tumor-suppressor-tsc1-is-a-new-hsp90-co-chaperone-that-facilitates-folding-of-kinase-and-non-kinase-clients
#9
Mark R Woodford, Rebecca A Sager, Elijah Marris, Diana M Dunn, Adam R Blanden, Ryan L Murphy, Nicholas Rensing, Oleg Shapiro, Barry Panaretou, Chrisostomos Prodromou, Stewart N Loh, David H Gutmann, Dimitra Bourboulia, Gennady Bratslavsky, Michael Wong, Mehdi Mollapour
The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC), a regulator of mTOR activity. Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains elusive. The molecular chaperone heat-shock protein 90 (Hsp90) is an essential component of the cellular homeostatic machinery in eukaryotes. Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity. The C-terminal domain of Tsc1 (998-1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain...
November 10, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29118001/real-time-detection-of-condensin-driven-dna-compaction-reveals-a-multistep-binding-mechanism
#10
Jorine M Eeftens, Shveta Bisht, Jacob Kerssemakers, Marc Kschonsak, Christian H Haering, Cees Dekker
Condensin, a conserved member of the SMC protein family of ring-shaped multi-subunit protein complexes, is essential for structuring and compacting chromosomes. Despite its key role, its molecular mechanism has remained largely unknown. Here, we employ single-molecule magnetic tweezers to measure, in real time, the compaction of individual DNA molecules by the budding yeast condensin complex. We show that compaction can proceed in large steps, driving DNA molecules into a fully condensed state against forces of up to 2 pN...
November 8, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29118000/ca-2-calmodulin-binding-to-psd-95-mediates-homeostatic-synaptic-scaling-down
#11
Dhrubajyoti Chowdhury, Matthew Turner, Tommaso Patriarchi, Anne C Hergarden, David Anderson, Yonghong Zhang, Junqing Sun, Chao-Yin Chen, James B Ames, Johannes W Hell
Postsynaptic density protein-95 (PSD-95) localizes AMPA-type glutamate receptors (AMPARs) to postsynaptic sites of glutamatergic synapses. Its postsynaptic displacement is necessary for loss of AMPARs during homeostatic scaling down of synapses. Here, we demonstrate that upon Ca(2+) influx, Ca(2+)/calmodulin (Ca(2+)/CaM) binding to the N-terminus of PSD-95 mediates postsynaptic loss of PSD-95 and AMPARs during homeostatic scaling down. Our NMR structural analysis identified E17 within the PSD-95 N-terminus as important for binding to Ca(2+)/CaM by interacting with R126 on CaM...
November 8, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29109154/hierarchical-protein-targeting-and-secretion-is-controlled-by-an-affinity-switch-in-the-type-iii-secretion-system-of-enteropathogenic-escherichia-coli
#12
Athina G Portaliou, Konstantinos C Tsolis, Maria S Loos, Vassileia Balabanidou, Josep Rayo, Alexandra Tsirigotaki, Valerie F Crepin, Gad Frankel, Charalampos G Kalodimos, Spyridoula Karamanou, Anastassios Economou
Type III secretion (T3S), a protein export pathway common to Gram-negative pathogens, comprises a trans-envelope syringe, the injectisome, with a cytoplasm-facing translocase channel. Exported substrates are chaperone-delivered to the translocase, EscV in enteropathogenic Escherichia coli, and cross it in strict hierarchical manner, for example, first "translocators", then "effectors". We dissected T3S substrate targeting and hierarchical switching by reconstituting them in vitro using inverted inner membrane vesicles...
November 6, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29101295/a-genetically-distinct-microglial-subset-promotes-myelination
#13
Mariko L Bennett, Ben A Barres
No abstract text is available yet for this article.
November 3, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29084722/dna-damage-induced-by-topoisomerase-inhibitors-activates-samhd1-and-blocks-hiv-1-infection-of-macrophages
#14
Petra Mlcochova, Sarah J Caswell, Ian A Taylor, Greg J Towers, Ravindra K Gupta
We report that DNA damage induced by topoisomerase inhibitors, including etoposide (ETO), results in a potent block to HIV-1 infection in human monocyte-derived macrophages (MDM). SAMHD1 suppresses viral reverse transcription (RT) through depletion of cellular dNTPs but is naturally switched off by phosphorylation in a subpopulation of MDM found in a G1-like state. We report that SAMHD1 was activated by dephosphorylation following ETO treatment, along with loss of expression of MCM2 and CDK1, and reduction in dNTP levels...
October 30, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29079701/mutational-signatures-of-non-homologous-and-polymerase-theta-mediated-end-joining-in-embryonic-stem-cells
#15
Joost Schimmel, Hanneke Kool, Robin van Schendel, Marcel Tijsterman
Cells employ potentially mutagenic DNA repair mechanisms to avoid the detrimental effects of chromosome breaks on cell survival. While classical non-homologous end-joining (cNHEJ) is largely error-free, alternative end-joining pathways have been described that are intrinsically mutagenic. Which end-joining mechanisms operate in germ and embryonic cells and thus contribute to heritable mutations found in congenital diseases is, however, still largely elusive. Here, we determined the genetic requirements for the repair of CRISPR/Cas9-induced chromosomal breaks of different configurations, and establish the mutational consequences...
October 27, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29074627/isoform-specific-localization-of-dnmt3a-regulates-dna-methylation-fidelity-at-bivalent-cpg-islands
#16
Massimiliano Manzo, Joël Wirz, Christina Ambrosi, Rodrigo Villaseñor, Bernd Roschitzki, Tuncay Baubec
DNA methylation is a prevalent epigenetic modification involved in transcriptional regulation and essential for mammalian development. While the genome-wide distribution of this mark has been studied to great detail, the mechanisms responsible for its correct deposition, as well as the cause for its aberrant localization in cancers, have not been fully elucidated. Here, we have compared the activity of individual DNMT3A isoforms in mouse embryonic stem and neuronal progenitor cells and report that these isoforms differ in their genomic binding and DNA methylation activity at regulatory sites...
October 26, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29074626/human-tho-sin3a-interaction-reveals-new-mechanisms-to-prevent-r-loops-that-cause-genome%C3%A2-instability
#17
Irene Salas-Armenteros, Carmen Pérez-Calero, Aleix Bayona-Feliu, Emanuela Tumini, Rosa Luna, Andrés Aguilera
R-loops, formed by co-transcriptional DNA-RNA hybrids and a displaced DNA single strand (ssDNA), fulfill certain positive regulatory roles but are also a source of genomic instability. One key cellular mechanism to prevent R-loop accumulation centers on the conserved THO/TREX complex, an RNA-binding factor involved in transcription elongation and RNA export that contributes to messenger ribonucleoprotein (mRNP) assembly, but whose precise function is still unclear. To understand how THO restrains harmful R-loops, we searched for new THO-interacting factors...
October 26, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29061763/a-tnf-p100-pathway-subverts-noncanonical-nf-%C3%AE%C2%BAb-signaling-in-inflamed-secondary-lymphoid-organs
#18
Tapas Mukherjee, Budhaditya Chatterjee, Atika Dhar, Sachendra S Bais, Meenakshi Chawla, Payel Roy, Anna George, Vineeta Bal, Satyajit Rath, Soumen Basak
Lymphotoxin-beta receptor (LTβR) present on stromal cells engages the noncanonical NF-κB pathway to mediate RelB-dependent expressions of homeostatic chemokines, which direct steady-state ingress of naïve lymphocytes to secondary lymphoid organs (SLOs). In this pathway, NIK promotes partial proteolysis of p100 into p52 that induces nuclear translocation of the RelB NF-κB heterodimers. Microbial infections often deplete homeostatic chemokines; it is thought that infection-inflicted destruction of stromal cells results in the downregulation of these chemokines...
October 23, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29054852/selective-base-excision-repair-of-dna-damage-by-the-non-base-flipping-dna-glycosylase-alkc
#19
Rongxin Shi, Elwood A Mullins, Xing-Xing Shen, Kori T Lay, Philip K Yuen, Sheila S David, Antonis Rokas, Brandt F Eichman
DNA glycosylases preserve genome integrity and define the specificity of the base excision repair pathway for discreet, detrimental modifications, and thus, the mechanisms by which glycosylases locate DNA damage are of particular interest. Bacterial AlkC and AlkD are specific for cationic alkylated nucleobases and have a distinctive HEAT-like repeat (HLR) fold. AlkD uses a unique non-base-flipping mechanism that enables excision of bulky lesions more commonly associated with nucleotide excision repair. In contrast, AlkC has a much narrower specificity for small lesions, principally N3-methyladenine (3mA)...
October 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29051229/channel-surfing-uncovers-a-dual-use-transporter
#20
Daniel L Minor
No abstract text is available yet for this article.
October 19, 2017: EMBO Journal
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