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https://www.readbyqxmd.com/read/28637794/a-trpv1-to-secretagogin-regulatory-axis-controls-pancreatic-%C3%AE-cell-survival-by-modulating-protein-turnover
#1
Katarzyna Malenczyk, Fatima Girach, Edit Szodorai, Petter Storm, Åsa Segerstolpe, Giuseppe Tortoriello, Robert Schnell, Jan Mulder, Roman A Romanov, Erzsébet Borók, Fabiana Piscitelli, Vincenzo Di Marzo, Gábor Szabó, Rickard Sandberg, Stefan Kubicek, Gert Lubec, Tomas Hökfelt, Ludwig Wagner, Leif Groop, Tibor Harkany
Ca(2+)-sensor proteins are generally implicated in insulin release through SNARE interactions. Here, secretagogin, whose expression in human pancreatic islets correlates with their insulin content and the incidence of type 2 diabetes, is shown to orchestrate an unexpectedly distinct mechanism. Single-cell RNA-seq reveals retained expression of the TRP family members in β-cells from diabetic donors. Amongst these, pharmacological probing identifies Ca(2+)-permeable transient receptor potential vanilloid type 1 channels (TRPV1) as potent inducers of secretagogin expression through recruitment of Sp1 transcription factors...
June 21, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28637793/endothelial-cell-metabolism-in-health-and-disease-impact-of-hypoxia
#2
REVIEW
Brian W Wong, Elke Marsch, Lucas Treps, Myriam Baes, Peter Carmeliet
In contrast to the general belief, endothelial cell (EC) metabolism has recently been identified as a driver rather than a bystander effect of angiogenesis in health and disease. Indeed, different EC subtypes present with distinct metabolic properties, which determine their function in angiogenesis upon growth factor stimulation. One of the main stimulators of angiogenesis is hypoxia, frequently observed in disease settings such as cancer and atherosclerosis. It has long been established that hypoxic signalling and metabolism changes are highly interlinked...
June 21, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28623242/oh-myeloid-immune-cells-wreaking-havoc-on-brain-homeostasis
#3
Liana Bonanno, Tony Wyss-Coray
No abstract text is available yet for this article.
June 16, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28623241/suppressing-mtorc1-on-the-lysosome
#4
Camilla Raiborg, Kay O Schink, Harald Stenmark
No abstract text is available yet for this article.
June 16, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28623240/adipose-tissue-between-the-extremes
#5
REVIEW
Alexandros Vegiopoulos, Maria Rohm, Stephan Herzig
Adipose tissue represents a critical component in healthy energy homeostasis. It fulfills important roles in whole-body lipid handling, serves as the body's major energy storage compartment and insulation barrier, and secretes numerous endocrine mediators such as adipokines or lipokines. As a consequence, dysfunction of these processes in adipose tissue compartments is tightly linked to severe metabolic disorders, including obesity, metabolic syndrome, lipodystrophy, and cachexia. While numerous studies have addressed causes and consequences of obesity-related adipose tissue hypertrophy and hyperplasia for health, critical pathways and mechanisms in (involuntary) adipose tissue loss as well as its systemic metabolic consequences are far less understood...
June 16, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28607005/opa1-deficiency-promotes-secretion-of-fgf21-from-muscle-that-prevents-obesity-and-insulin-resistance
#6
Renata Oliveira Pereira, Satya M Tadinada, Frederick M Zasadny, Karen Jesus Oliveira, Karla Maria Pereira Pires, Angela Olvera, Jennifer Jeffers, Rhonda Souvenir, Rose Mcglauflin, Alec Seei, Trevor Funari, Hiromi Sesaki, Matthew J Potthoff, Christopher M Adams, Ethan J Anderson, E Dale Abel
Mitochondrial dynamics is a conserved process by which mitochondria undergo repeated cycles of fusion and fission, leading to exchange of mitochondrial genetic content, ions, metabolites, and proteins. Here, we examine the role of the mitochondrial fusion protein optic atrophy 1 (OPA1) in differentiated skeletal muscle by reducing OPA1 gene expression in an inducible manner. OPA1 deficiency in young mice results in non-lethal progressive mitochondrial dysfunction and loss of muscle mass. Mutant mice are resistant to age- and diet-induced weight gain and insulin resistance, by mechanisms that involve activation of ER stress and secretion of fibroblast growth factor 21 (FGF21) from skeletal muscle, resulting in increased metabolic rates and improved whole-body insulin sensitivity...
June 12, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28607004/rpa-activates-the-xpf-ercc1-endonuclease-to-initiate-processing-of-dna-interstrand-crosslinks
#7
Ummi B Abdullah, Joanna F McGouran, Sanja Brolih, Denis Ptchelkine, Afaf H El-Sagheer, Tom Brown, Peter J McHugh
During replication-coupled DNA interstrand crosslink (ICL) repair, the XPF-ERCC1 endonuclease is required for the incisions that release, or "unhook", ICLs, but the mechanism of ICL unhooking remains largely unknown. Incisions are triggered when the nascent leading strand of a replication fork strikes the ICL Here, we report that while purified XPF-ERCC1 incises simple ICL-containing model replication fork structures, the presence of a nascent leading strand, modelling the effects of replication arrest, inhibits this activity...
June 12, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28607003/p21-maintains-senescent-cell-viability-under-persistent-dna-damage-response-by-restraining-jnk-and-caspase-signaling
#8
Reut Yosef, Noam Pilpel, Nurit Papismadov, Hilah Gal, Yossi Ovadya, Ezra Vadai, Stav Miller, Ziv Porat, Shifra Ben-Dor, Valery Krizhanovsky
Cellular senescence is a permanent state of cell cycle arrest that protects the organism from tumorigenesis and regulates tissue integrity upon damage and during tissue remodeling. However, accumulation of senescent cells in tissues during aging contributes to age-related pathologies. A deeper understanding of the mechanisms regulating the viability of senescent cells is therefore required. Here, we show that the CDK inhibitor p21 (CDKN1A) maintains the viability of DNA damage-induced senescent cells. Upon p21 knockdown, senescent cells acquired multiple DNA lesions that activated ataxia telangiectasia mutated (ATM) and nuclear factor (NF)-κB kinase, leading to decreased cell survival...
June 12, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28607002/atm-wip1-activities-at-chromatin-control-plk1-re-activation-to-determine-g2-checkpoint-duration
#9
Himjyot Jaiswal, Jan Benada, Erik Müllers, Karen Akopyan, Kamila Burdova, Tobias Koolmeister, Thomas Helleday, René H Medema, Libor Macurek, Arne Lindqvist
After DNA damage, the cell cycle is arrested to avoid propagation of mutations. Arrest in G2 phase is initiated by ATM-/ATR-dependent signaling that inhibits mitosis-promoting kinases such as Plk1. At the same time, Plk1 can counteract ATR-dependent signaling and is required for eventual resumption of the cell cycle. However, what determines when Plk1 activity can resume remains unclear. Here, we use FRET-based reporters to show that a global spread of ATM activity on chromatin and phosphorylation of ATM targets including KAP1 control Plk1 re-activation...
June 12, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28596378/molecular-definitions-of-autophagy-and-related-processes
#10
REVIEW
Lorenzo Galluzzi, Eric H Baehrecke, Andrea Ballabio, Patricia Boya, José Manuel Bravo-San Pedro, Francesco Cecconi, Augustine M Choi, Charleen T Chu, Patrice Codogno, Maria Isabel Colombo, Ana Maria Cuervo, Jayanta Debnath, Vojo Deretic, Ivan Dikic, Eeva-Liisa Eskelinen, Gian Maria Fimia, Simone Fulda, David A Gewirtz, Douglas R Green, Malene Hansen, J Wade Harper, Marja Jäättelä, Terje Johansen, Gabor Juhasz, Alec C Kimmelman, Claudine Kraft, Nicholas T Ktistakis, Sharad Kumar, Beth Levine, Carlos Lopez-Otin, Frank Madeo, Sascha Martens, Jennifer Martinez, Alicia Melendez, Noboru Mizushima, Christian Münz, Leon O Murphy, Josef M Penninger, Mauro Piacentini, Fulvio Reggiori, David C Rubinsztein, Kevin M Ryan, Laura Santambrogio, Luca Scorrano, Anna Katharina Simon, Hans-Uwe Simon, Anne Simonsen, Nektarios Tavernarakis, Sharon A Tooze, Tamotsu Yoshimori, Junying Yuan, Zhenyu Yue, Qing Zhong, Guido Kroemer
Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field...
June 8, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28588064/autotaxin-lysophosphatidic-acid-lpa3-signaling-at-the-embryo-epithelial-boundary-controls-decidualization-pathways
#11
Shizu Aikawa, Kuniyuki Kano, Asuka Inoue, Jiao Wang, Daisuke Saigusa, Takeshi Nagamatsu, Yasushi Hirota, Tomoyuki Fujii, Soken Tsuchiya, Yoshitaka Taketomi, Yukihiko Sugimoto, Makoto Murakami, Makoto Arita, Makoto Kurano, Hitoshi Ikeda, Yutaka Yatomi, Jerold Chun, Junken Aoki
During pregnancy, up-regulation of heparin-binding (HB-) EGF and cyclooxygenase-2 (COX-2) in the uterine epithelium contributes to decidualization, a series of uterine morphological changes required for placental formation and fetal development. Here, we report a key role for the lipid mediator lysophosphatidic acid (LPA) in decidualization, acting through its G-protein-coupled receptor LPA3 in the uterine epithelium. Knockout of Lpar3 or inhibition of the LPA-producing enzyme autotaxin (ATX) in pregnant mice leads to HB-EGF and COX-2 down-regulation near embryos and attenuates decidual reactions...
June 6, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28572448/structural-and-functional-dissection-of-the-interplay-between-lipid-and-notch-binding-by-human-notch-ligands
#12
Richard J Suckling, Boguslawa Korona, Pat Whiteman, Chandramouli Chillakuri, Laurie Holt, Penny A Handford, Susan M Lea
Recent data have expanded our understanding of Notch signalling by identifying a C2 domain at the N-terminus of Notch ligands, which has both lipid- and receptor-binding properties. We present novel structures of human ligands Jagged2 and Delta-like4 and human Notch2, together with functional assays, which suggest that ligand-mediated coupling of membrane recognition and Notch binding is likely to be critical in establishing the optimal context for Notch signalling. Comparisons between the Jagged and Delta family show a huge diversity in the structures of the loops at the apex of the C2 domain implicated in membrane recognition and Jagged1 missense mutations, which affect these loops and are associated with extrahepatic biliary atresia, lead to a loss of membrane recognition, but do not alter Notch binding...
June 1, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28559417/the-ftd-like-syndrome-causing-trem2-t66m-mutation-impairs-microglia-function-brain-perfusion-and-glucose-metabolism
#13
Gernot Kleinberger, Matthias Brendel, Eva Mracsko, Benedikt Wefers, Linda Groeneweg, Xianyuan Xiang, Carola Focke, Maximilian Deußing, Marc Suárez-Calvet, Fargol Mazaheri, Samira Parhizkar, Nadine Pettkus, Wolfgang Wurst, Regina Feederle, Peter Bartenstein, Thomas Mueggler, Thomas Arzberger, Irene Knuesel, Axel Rominger, Christian Haass
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD-like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for the disease-associated Trem2 p.T66M mutation. Consistent with a loss-of-function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p...
May 30, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28559416/in-vitro-expansion-of-mouse-primordial-germ-cell-like-cells-recapitulates-an-epigenetic-blank-slate
#14
Hiroshi Ohta, Kazuki Kurimoto, Ikuhiro Okamoto, Tomonori Nakamura, Yukihiro Yabuta, Hidetaka Miyauchi, Takuya Yamamoto, Yukiko Okuno, Masatoshi Hagiwara, Kenjiro Shirane, Hiroyuki Sasaki, Mitinori Saitou
The expansion of primordial germ cells (PGCs), the precursors for the oocytes and spermatozoa, is a key challenge in reproductive biology/medicine. Using a chemical screening exploiting PGC-like cells (PGCLCs) induced from mouse embryonic stem cells (ESCs), we here identify key signaling pathways critical for PGCLC proliferation. We show that the combinatorial application of Forskolin and Rolipram, which stimulate cAMP signaling via different mechanisms, expands PGCLCs up to ~50-fold in culture. The expanded PGCLCs maintain robust capacity for spermatogenesis, rescuing the fertility of infertile mice...
May 30, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28554895/par-1-promotes-microtubule-breakdown-during-dendrite-pruning-in-drosophila
#15
Svende Herzmann, Rafael Krumkamp, Sandra Rode, Carina Kintrup, Sebastian Rumpf
Pruning of unspecific neurites is an important mechanism during neuronal morphogenesis. Drosophila sensory neurons prune their dendrites during metamorphosis. Pruning dendrites are severed in their proximal regions. Prior to severing, dendritic microtubules undergo local disassembly, and dendrites thin extensively through local endocytosis. Microtubule disassembly requires a katanin homologue, but the signals initiating microtubule breakdown are not known. Here, we show that the kinase PAR-1 is required for pruning and dendritic microtubule breakdown...
May 29, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28554894/fam60a-defines-a-variant-sin3a-hdac-complex-in-embryonic-stem-cells-required-for-self-renewal
#16
Gundula Streubel, Darren J Fitzpatrick, Giorgio Oliviero, Andrea Scelfo, Bruce Moran, Sudipto Das, Nayla Munawar, Ariane Watson, Kieran Wynne, Gian Luca Negri, Eugene T Dillon, SriGanesh Jammula, Karsten Hokamp, Darran P O'Connor, Diego Pasini, Gerard Cagney, Adrian P Bracken
Sin3a is the central scaffold protein of the prototypical Hdac1/2 chromatin repressor complex, crucially required during early embryonic development for the growth of pluripotent cells of the inner cell mass. Here, we compare the composition of the Sin3a-Hdac complex between pluripotent embryonic stem (ES) and differentiated cells by establishing a method that couples two independent endogenous immunoprecipitations with quantitative mass spectrometry. We define the precise composition of the Sin3a complex in multiple cell types and identify the Fam60a subunit as a key defining feature of a variant Sin3a complex present in ES cells, which also contains Ogt and Tet1...
May 29, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28550152/er-plasma-membrane-contact-sites-contribute-to-autophagosome-biogenesis-by-regulation-of-local-pi3p-synthesis
#17
Anna Chiara Nascimbeni, Francesca Giordano, Nicolas Dupont, Daniel Grasso, Maria I Vaccaro, Patrice Codogno, Etienne Morel
The double-membrane-bound autophagosome is formed by the closure of a structure called the phagophore, origin of which is still unclear. The endoplasmic reticulum (ER) is clearly implicated in autophagosome biogenesis due to the presence of the omegasome subdomain positive for DFCP1, a phosphatidyl-inositol-3-phosphate (PI3P) binding protein. Contribution of other membrane sources, like the plasma membrane (PM), is still difficult to integrate in a global picture. Here we show that ER-plasma membrane contact sites are mobilized for autophagosome biogenesis, by direct implication of the tethering extended synaptotagmins (E-Syts) proteins...
May 26, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28533229/intrinsic-regulation-of-enteroendocrine-fate-by-numb
#18
Jérémy Sallé, Louis Gervais, Benjamin Boumard, Marine Stefanutti, Katarzyna Siudeja, Allison J Bardin
How terminal cell fates are specified in dynamically renewing adult tissues is not well understood. Here we explore terminal cell fate establishment during homeostasis using the enteroendocrine cells (EEs) of the adult Drosophila midgut as a paradigm. Our data argue against the existence of local feedback signals, and we identify Numb as an intrinsic regulator of EE fate. Our data further indicate that Numb, with alpha-adaptin, acts upstream or in parallel of known regulators of EE fate to limit Notch signaling, thereby facilitating EE fate acquisition...
May 22, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28515121/ampk%C3%AE-1-ldh-pathway-regulates-muscle-stem-cell-self-renewal-by-controlling-metabolic-homeostasis
#19
Marine Theret, Linda Gsaier, Bethany Schaffer, Gaëtan Juban, Sabrina Ben Larbi, Michèle Weiss-Gayet, Laurent Bultot, Collodet Caterina, Marc Foretz, Dominique Desplanches, Pascual Sanz, Zizhao Zang, Lin Yang, Guillaume Vial, Benoit Viollet, Kei Sakamoto, Anne Brunet, Bénédicte Chazaud, Rémi Mounier
Control of stem cell fate to either enter terminal differentiation versus returning to quiescence (self-renewal) is crucial for tissue repair. Here, we showed that AMP-activated protein kinase (AMPK), the master metabolic regulator of the cell, controls muscle stem cell (MuSC) self-renewal. AMPKα1(-/-) MuSCs displayed a high self-renewal rate, which impairs muscle regeneration. AMPKα1(-/-) MuSCs showed a Warburg-like switch of their metabolism to higher glycolysis. We identified lactate dehydrogenase (LDH) as a new functional target of AMPKα1...
May 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28507225/phosphorylation-of-pkp1-by-ripk4-regulates-epidermal-differentiation-and-skin-tumorigenesis
#20
Philbert Lee, Shangwen Jiang, Yuanyuan Li, Jiping Yue, Xuewen Gou, Shao-Yu Chen, Yingming Zhao, Markus Schober, Minjia Tan, Xiaoyang Wu
Tissue homeostasis of skin is sustained by epidermal progenitor cells localized within the basal layer of the skin epithelium. Post-translational modification of the proteome, such as protein phosphorylation, plays a fundamental role in the regulation of stemness and differentiation of somatic stem cells. However, it remains unclear how phosphoproteomic changes occur and contribute to epidermal differentiation. In this study, we survey the epidermal cell differentiation in a systematic manner by combining quantitative phosphoproteomics with mammalian kinome cDNA library screen...
May 15, 2017: EMBO Journal
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