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| Open AccessDesmosomal cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination
The epidermis is a multi-layered epithelium formed by the differentiation of basal cells and movement into suprabasal layers. Here the authors define a role for the desmosomal cadherin desmoglein-1 in promoting the delamination of basal cells by remodeling the actin cytoskeleton through interactions with the dynein light chain Tctex-1 and cortactin.
- Oxana Nekrasova
- , Robert M. Harmon
- & Kathleen J. Green
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Article
| Open AccessFunctionally distinct and selectively phosphorylated GPCR subpopulations co-exist in a single cell
β2-adrenergic receptor (β2AR) can be phosphorylated by G protein receptor kinases and second messenger-dependent kinases. Here, the authors demonstrate that these phosphorylation events are specific to functionally distinct and spatially segregated subpopulations of β2AR that co-exist in a single cell.
- Ao Shen
- , Madeline Nieves-Cintron
- & Yang K. Xiang
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Article
| Open AccessA LATS biosensor screen identifies VEGFR as a regulator of the Hippo pathway in angiogenesis
The Hippo pathway is a major orchestrator of organ development and homeostasis. Here Azad and colleagues develop a biosensor to monitor the activity of the Hippo pathway component LATS and identify VEGF signalling as an upstream regulator of LATS, supporting a role for Hippo signalling during angiogenesis.
- T. Azad
- , H. J. Janse van Rensburg
- & X. Yang
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Article
| Open AccessAtrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling
ATRX inactivation frequently occurs in glioma. Here, the authors explore the role of ATRX inactivation in oncogenesis, highlighting ATRX deficiency driven epigenomic changes that influence the expression of genes crucial to the oncogenic phenotype.
- Carla Danussi
- , Promita Bose
- & Jason T. Huse
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Article
| Open AccessBenchmarking common quantification strategies for large-scale phosphoproteomics
Quantitative phosphoproteomics has become a standard method in molecular and cell biology. Here, the authors compare performance and parameters of phosphoproteome quantification by LFQ, SILAC, and MS2-/MS3-based TMT and introduce a TMT-adapted algorithm for calculating phosphorylation site stoichiometry.
- Alexander Hogrebe
- , Louise von Stechow
- & Jesper V. Olsen
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Article
| Open AccessCoA synthase regulates mitotic fidelity via CBP-mediated acetylation
The temporal activation of kinases and timely ubiquitin-mediated degradation is central to faithful mitosis. Here the authors show that acetylation controlled by Coenzyme A synthase (COASY) and acetyltransferase CBP constitutes a mechanism that ensures faithful mitosis.
- Chao-Chieh Lin
- , Mayumi Kitagawa
- & Jen-Tsan Chi
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Article
| Open AccessParacrine cellular senescence exacerbates biliary injury and impairs regeneration
Senescence has been suggested as causing biliary cholangiopathies but how this is regulated is unclear. Here, the authors generate a mouse model of biliary senescence by deleting Mdm2 in bile ducts and show that inhibiting TGFβ limits senescence-dependent aggravation of cholangiopathies.
- Sofia Ferreira-Gonzalez
- , Wei-Yu Lu
- & Stuart J. Forbes
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Article
| Open AccessCDK6 inhibits white to beige fat transition by suppressing RUNX1
Beige adipocytes can arise from transdifferentiation of mature white adipocytes. Here the authors identify CDK6 as a key molecule involved in the white-to-beige adipocyte transdifferentiation and, therefore, as a regulator of organismal energy homeostasis in mice.
- Xiaoli Hou
- , Yongzhao Zhang
- & Miaofen G. Hu
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Article
| Open AccessInsc:LGN tetramers promote asymmetric divisions of mammary stem cells
During asymmetric divisions fate determinants and niche contacts segregate unequally between daughter cells, but the mechanism is unclear. Here the authors show that Insc:LGN tetramers promote assembly of Par3-Insc-LGN-GαiGDP complexes and asymmetric fate specification independently of microtubule motors.
- Simone Culurgioni
- , Sara Mari
- & Marina Mapelli
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Article
| Open Accessp63 is a key regulator of iRHOM2 signalling in the keratinocyte stress response
Mutations in the gene encoding iRHOM2 are associated with hyperproliferative epidermal disorders. Here, the authors show that iRHOM2 is a target gene of p63, that together they regulate inflammation, cell survival and response to oxidative stress, and inhibition of p63-iRHOM2 signalling with an antioxidant reduces epidermal inflammation.
- Paola Arcidiacono
- , Catherine M. Webb
- & Anissa Chikh
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Article
| Open AccessPhosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting
Sorting nexin 3 (SNX3) is a phosphatidylinositol 3-phosphate binding protein that localizes to early endosomes. Here the authors use NMR to resolve SNX3′s membrane interactions, revealing that membrane binding is regulated through phosphorylation of a conserved serine by its lipid recognition site.
- Marc Lenoir
- , Cansel Ustunel
- & Michael Overduin
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Article
| Open AccessAn HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm
Vascular smooth muscle cell (VSMC) dysfunction is a common feature of thoracic aortic aneurysms (TAAs). Here, Lino Cardenas and colleagues show that the formation of a HDAC9-MALAT1-BRG1 complex promotes VSMC dysfunction in TAA by epigenetically altering the expression of key components of the cytoskeleton in VSMCs.
- Christian L. Lino Cardenas
- , Chase W. Kessinger
- & Mark E. Lindsay
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Article
| Open AccessA conserved interaction of the dynein light intermediate chain with dynein-dynactin effectors necessary for processivity
A growing number of cargo-specific effector proteins are being identified that interact with both dynein and dynactin and form processive dynein-dynactin-effector complexes. Here the authors identify and characterize a conserved mechanism of interaction between dynein and unrelated effector proteins.
- In-Gyun Lee
- , Mara A. Olenick
- & Roberto Dominguez
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Article
| Open AccessUncovering the balance of forces driving microtubule aster migration in C. elegans zygotes
Microtubule asters are positioned precisely within cells by forces generated by molecular motors, but it is unclear how these are integrated in space and time. Here the authors perform in vivo drag measurements and genetic manipulations to determine the balance of forces that position microtubule asters in C. elegans zygotes.
- A. De Simone
- , A. Spahr
- & P. Gönczy
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Article
| Open AccessMAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB
Amino acids stimulate cell growth and depletion in a cell activates autophagy, yet how this is regulated is unclear. Here, the authors show that MAP4K3 (also known as germinal-center kinase-like kinase) acts as an amino acid-dependent regulator of autophagy, via phosphorylation of the transcription factor EB.
- Cynthia L. Hsu
- , Elian X. Lee
- & Albert R. La Spada
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Article
| Open AccessMT4-MMP deficiency increases patrolling monocyte recruitment to early lesions and accelerates atherosclerosis
Matrix metalloproteinases (MMP) are involved in vascular remodeling associated with plaque progression. Little is known about their immune regulatory role in vascular disorders. Here, the authors report that MT4-MMP-deficiency increases the recruitment of patrolling monocytes to early atherosclerotic lesions, which accelerates atherosclerosis.
- Cristina Clemente
- , Cristina Rius
- & Alicia G. Arroyo
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Article
| Open AccessA peptide tag-specific nanobody enables high-quality labeling for dSTORM imaging
Nanobodies (Nbs) coupled to organic dyes are increasingly used for super-resolution cell imaging, but producing gene-specific Nbs is time-consuming. Here the authors present a peptide-tag/Nb combination for dSTORM imaging which can be easily adapted to different targets in fixed and live cells.
- David Virant
- , Bjoern Traenkle
- & Ulrich Rothbauer
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Article
| Open AccessConserved roles of C. elegans and human MANFs in sulfatide binding and cytoprotection
MANF is a secreted ER stress-inducible protein that protects neurons, pancreatic β cells and cardiomyocytes from cell death under oxidative stress, hypoxic or ischemic conditions. Here the authors show that MANF confers cytoprotection through direct binding to sulfatide followed by cellular uptake in both C. elegans and mammalian cells.
- Meirong Bai
- , Roman Vozdek
- & Dengke K. Ma
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Article
| Open AccessUnattached kinetochores drive their own capturing by sequestering a CLASP
Kinetochores (KT) that are not attached to microtubules prevent chromosome missegregation via the spindle assembly checkpoint. Here the authors show that Mps1 localizes Stu1 at unattached KTs together with Slk19, causing a reorganization of the nuclear MT network that favors the capturing of unattached KT.
- Caroline Kolenda
- , Jennifer Ortiz
- & Johannes Lechner
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Article
| Open AccessSingle cell polarity in liquid phase facilitates tumour metastasis
Polarisation of metastasising cancer cells in circulation has not been investigated before. Here the authors identify single cell polarity as a distinct polarisation state of single cells in liquid phase, and show that perturbing single cell polarity affects attachment, adhesion, transmigration and metastasis in vitro and in vivo.
- Anna Lorentzen
- , Paul F. Becker
- & Mathias Heikenwalder
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Article
| Open AccessHigh capacity in G protein-coupled receptor signaling
G protein-coupled receptors (GPCRs) activate intracellular signalling pathways upon extracellular stimulation. Here authors record single cell responses of GPCR signalling which allows the direct estimation of its channel capacity for each cell along with the reproducibility of its response.
- Amiran Keshelava
- , Gonzalo P. Solis
- & Vladimir L. Katanaev
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Article
| Open AccessEGFL7 reduces CNS inflammation in mouse
Endothelial cells release extracellular matrix components that regulate inflammation. Here the authors demonstrate that the extracellular matrix component epidermal growth factor-like protein 7 regulates inflammation in experimental autoimmune encephalomyelitis in the mouse.
- Catherine Larochelle
- , Timo Uphaus
- & Frauke Zipp
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Article
| Open AccessA cryptic RNA-binding domain mediates Syncrip recognition and exosomal partitioning of miRNA targets
Syncrip is a conserved RNA-binding protein that mediates selective miRNA loading into cell-secreted exosomes, which is important for cell–cell communication. Here the authors provide mechanistic insights into how Syncrip recognises its target miRNAs by combining NMR and crystallography.
- Fruzsina Hobor
- , Andre Dallmann
- & Andres Ramos
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Article
| Open AccessA dual mechanism promotes switching of the Stormorken STIM1 R304W mutant into the activated state
Stormorken syndrome is associated with the R304W mutation in STIM1, which is a Calcium sensor in the endoplasmic reticulum. Here authors use FRET and electrophysiology to show that R304W induces STIM1 conformational extension by a dual mechanism resulting in constitutive activation of Ca2+ channels.
- Marc Fahrner
- , Michael Stadlbauer
- & Christoph Romanin
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Article
| Open AccessCardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein
Cardiolipin is a phospholipid component of the inner mitochondrial membrane. Here the authors demonstrate that cardiolipin interacts with mutant α-synuclein, and that impaired cardiolipin function can lead to spread of α-synuclein between neurons.
- Tammy Ryan
- , Vladimir V. Bamm
- & Scott D. Ryan
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Article
| Open AccessHypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens myocardial ischemia-reperfusion injury
Myocardial ischemia–reperfusion injury stabilizes the hypoxia-inducible factor HIF2-alpha. Here, the authors show that HIF2-alpha protects the heart from injury via induction of the epidermal growth factor amphiregulin, and that amphiregulin administration is cardioprotective in mice.
- Michael Koeppen
- , Jae W. Lee
- & Holger K. Eltzschig
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Article
| Open AccessVps3 and Vps8 control integrin trafficking from early to recycling endosomes and regulate integrin-dependent functions
The CORVET complex is a multi-subunit complex that regulates fusion between early endosomes. Here the authors show that the CORVET subunits Vps3 and Vps8 also regulate vesicular transport from early to recycling endosomes and are required for recycling integrins to the plasma membrane.
- Caspar T. H. Jonker
- , Romain Galmes
- & Judith Klumperman
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Article
| Open AccessA family of unconventional deubiquitinases with modular chain specificity determinants
Deubiquitinating enzymes (DUBs) are essential to modulate ubiquitin signaling. While known DUBs can be grouped into six families, the authors here present biochemical and structural evidence for a seventh DUB family, defining determinants of substrate specificity for two representative enzymes.
- Thomas Hermanns
- , Christian Pichlo
- & Kay Hofmann
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Article
| Open AccessMembrane cholesterol mediates the cellular effects of monolayer graphene substrates
Understanding the biological role of graphene in eukaryotic cells is essential for future biomedicine applications. Here, the authors investigate the interaction of neurons and fibroblasts with graphene substrates, which increase cell membrane cholesterol and potentiate neurotransmitter release and receptor signaling.
- Kristina E. Kitko
- , Tu Hong
- & Qi Zhang
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Article
| Open AccessThe structure of iPLA2β reveals dimeric active sites and suggests mechanisms of regulation and localization
Calcium-independent phospholipase A2β (iPLA2β) is involved in many physiological and pathological processes but the underlying mechanisms are largely unknown. Here, the authors present the structure of dimeric iPLA2β, providing insights into the regulation of its activity and cellular localization.
- Konstantin R. Malley
- , Olga Koroleva
- & Sergey Korolev
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Article
| Open AccessEGF receptor kinase suppresses ciliogenesis through activation of USP8 deubiquitinase
The trichoplein-Aurora A pathway inhibits ciliogenesis in proliferating cells. Here the authors EGFR-mediated phosphorylation of the deubiquitinating enzyme USP8 leads to its activation, and this suppresses trichoplein degradation, allowing inhibition of ciliogenesis.
- Kousuke Kasahara
- , Hiromasa Aoki
- & Masaki Inagaki
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Article
| Open AccessSumoylation regulates FMRP-mediated dendritic spine elimination and maturation
Fragile X syndrome patients display intellectual disability and autism, caused by mutations in the RNA-binding protein fragile X mental retardation protein (FMRP). Here, the authors show that FMRP sumoylation is required for regulating spine density and maturation.
- Anouar Khayachi
- , Carole Gwizdek
- & Stéphane Martin
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Article
| Open AccessHDAC1 and HDAC2 integrate checkpoint kinase phosphorylation and cell fate through the phosphatase-2A subunit PR130
Checkpoint kinases control cell cycle progression via the regulation of many key regulators. Here the authors demonstrate how HDAC1 and HDAC2 modulate checkpoint kinase signalling via the suppression of PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2.
- Anja Göder
- , Claudia Emmerich
- & Oliver H. Krämer
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Article
| Open AccessBasal condensation of Numb and Pon complex via phase transition during Drosophila neuroblast asymmetric division
Polarized localization of Numb and Pon in Drosophila neuroblasts (NBs) enables their unequal segregation during asymmetric cell divisions. Here, the authors demonstrate liquid-liquid phase separation of Pon and Numb in NBs mediated by multivalent intermolecular interactions is required for their basal condensation.
- Zelin Shan
- , Yuting Tu
- & Wenyu Wen
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Article
| Open AccessLEM-3 is a midbody-tethered DNA nuclease that resolves chromatin bridges during late mitosis
Chromosome segregation and genome maintenance require the removal of DNA bridges that link chromosomes just before cells divide. Here the authors show that the LEM-3/Ankle1 nuclease processes DNA bridges before cells divide and define a previously undescribed genome integrity mechanism.
- Ye Hong
- , Remi Sonneville
- & Anton Gartner
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Article
| Open AccessSystematic analysis of protein turnover in primary cells
The proteome-wide characterization of proteostasis depends on robust approaches to determine protein half-lives. Here, the authors improve the accuracy and precision of mass spectrometry-based quantification, enabling reliable protein half-life determination in several non-dividing cell types.
- Toby Mathieson
- , Holger Franken
- & Mikhail M. Savitski
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Article
| Open AccessUSP35 regulates mitotic progression by modulating the stability of Aurora B
Aurora B kinase is a member of the chromosomal passenger complex, which is an indispensable regulator of mitosis. Here the authors show that the deubiquitinating enzyme USP35 has a role in mitotic progression by inhibiting proteasomal degradation of Aurora B kinase, leading to its activation.
- Jinyoung Park
- , Mi-Sun Kwon
- & Eun Joo Song
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Article
| Open AccessMutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human
Asthenozoospermia is a major cause of male infertility, and multiple morphological abnormalities of the flagella (MMAF) is a particularly severe form. Here, using whole-exome sequencing of 78 MMAF patients, the authors identify mutations in two WDR proteins, CFAP43 and CFAP44, and confirm that these proteins are required for flagellogenesis in mouse and Trypanosoma brucei.
- Charles Coutton
- , Alexandra S. Vargas
- & Pierre F. Ray
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Article
| Open Access53BP1 can limit sister-chromatid rupture and rearrangements driven by a distinct ultrafine DNA bridging-breakage process
Chromosome instability is associated with cancer formation. Here the authors identify in cultured human cancer cells a non-canonical DNA bridge breakage pathway leading to chromosome missegregation and rearrangements triggered by sister DNA intertwinements, which are limited by 53BP1.
- Ankana Tiwari
- , Owen Addis Jones
- & Kok-Lung Chan
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Article
| Open AccessNanobody-triggered lockdown of VSRs reveals ligand reloading in the Golgi
Vacuolar sorting receptors (VSRs) are suggested to efficiently transport hydrolases by continuous cycling. Here, the authors use a nanobody-epitope interaction-based labeling approach to trace VSR recycling from the TGN/EE to the cis-Golgi and reveal ligand reloading of recycled VSRs.
- Simone Früholz
- , Florian Fäßler
- & Peter Pimpl
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Article
| Open AccessCytosine modifications exhibit circadian oscillations that are involved in epigenetic diversity and aging
While epigenetic factors have been implicated in the circadian rhythm, the detection of circadian cytosine modifications has remained elusive. Here the authors identify a large number of epigenetically variable cytosines that show circadian oscillations in their modification status in mice.
- Gabriel Oh
- , Sasha Ebrahimi
- & Art Petronis
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Article
| Open AccessThe WDR11 complex facilitates the tethering of AP-1-derived vesicles
Trafficking from endosomes to the trans-Golgi network requires recognition of vesicle tethers during membrane docking. Here, the authors identify a complex localised to AP-1 generated vesicles containing WDR11, C17orf75 and FAM91A, which together with TBC1D23 facilitates vesicle capture on Golgi membranes
- Paloma Navarro Negredo
- , James R. Edgar
- & Margaret S. Robinson
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Article
| Open AccessThe IAP family member BRUCE regulates autophagosome–lysosome fusion
The inhibitor of apoptosis (IAP) protein, BRUCE is known to ubiquitinate apoptosis regulators for proteasomal degradation. Here the authors show that BRUCE provides a bridge between LAMP2 on lysosomes and Atg8 family proteins on autophagosomes to support autophagosome-lysosome fusion.
- Petra Ebner
- , Isabella Poetsch
- & Fumiyo Ikeda
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Article
| Open AccessSOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2α
Tumour vasculature influences drug delivery. Here, the authors show that SOD3 re-expression enhances doxorubicin delivery and effects through normalization of tumour vasculature via the HIF-2a/VE-cadherin pathway.
- Emilia Mira
- , Lorena Carmona-Rodríguez
- & Santos Mañes
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Article
| Open AccessA small molecule inhibitor of Rheb selectively targets mTORC1 signaling
Aberrant mTORC1 signaling is linked to several chronic diseases. Here, the authors develop a small molecule inhibitor that binds the small G-protein Rheb and selectively blocks mTORC1 signaling, holding potential for therapeutic applications.
- Sarah J. Mahoney
- , Sridhar Narayan
- & Eddine Saiah
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Article
| Open Accessα-cell glucokinase suppresses glucose-regulated glucagon secretion
Glucagon secretion is promoted during hypoglycemia and inhibited by increased glucose levels. Here, Basco et al. show that glucokinase suppresses glucose-regulated glucagon secretion by modulating the intracellular ATP/ADP ratio and the closure of KATP channels in α-cells.
- Davide Basco
- , Quan Zhang
- & Bernard Thorens
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Article
| Open AccessSirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner
Tumour metabolism can be controlled through post-translational modifications. Here the authors show that Sirtuin5 promotes glutaminolysis in colorectal cancer cells via glutamate dehydrogenase-1, a critical regulator of glutaminolysis, inducing its deglutarylation and functional activation.
- Yun-Qian Wang
- , Hao-Lian Wang
- & Jing-Yuan Fang
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Article
| Open AccessBRE/BRCC45 regulates CDC25A stability by recruiting USP7 in response to DNA damage
Loss of BRCA2 leads to cancer formation. Here, the authors use an insertional mutagenesis approach and identify a multiprotein complex consisting of BRE, USP7 and CDC25A that can support the survival of BRCA2-deficient cells.
- Kajal Biswas
- , Subha Philip
- & Shyam K. Sharan
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Article
| Open AccessLymphocyte-specific protein 1 regulates mechanosensory oscillation of podosomes and actin isoform-based actomyosin symmetry breaking
The actomyosin cytoskeleton plays an important role in polarised cell migration. Here the authors identify lymphocyte-specific protein (LSP)-1 as a regulator of actomyosin contractility in macrophages, by competing with supervillin for myosin IIA activators acting specifically on the β-actin isoform.
- Pasquale Cervero
- , Christiane Wiesner
- & Stefan Linder
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