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Article |
Kinase-controlled phase transition of membraneless organelles in mitosis
The dual-specificity kinase DYRK3 acts as a central ‘dissolvase’, mediating the phase transitions of several types of membraneless organelles during mitosis.
- Arpan Kumar Rai
- , Jia-Xuan Chen
- & Lucas Pelkmans
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Letter |
OTULIN limits cell death and inflammation by deubiquitinating LUBAC
OTULIN, which removes ubiquitin chains deposited by LUBAC, promotes LUBAC activity by preventing its auto-ubiquitination, thereby supporting normal mouse embryo development and preventing pro-inflammatory cell death in adult mice.
- Klaus Heger
- , Katherine E. Wickliffe
- & Vishva M. Dixit
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Letter |
Mechanism of parkin activation by PINK1
Structural mass spectrometry of full-length human parkin and a structure of the activated parkin core reveal large-scale domain rearrangements involved in activation of parkin by PINK1.
- Christina Gladkova
- , Sarah L. Maslen
- & David Komander
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Letter |
Mechanism of phosphoribosyl-ubiquitination mediated by a single Legionella effector
Crystal structures of the Legionella effectors SdeA and SdeD uncover the mechanism of a unique phosphoribosyl-ubiquitination reaction.
- Anil Akturk
- , David J. Wasilko
- & Yuxin Mao
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Letter |
Insights into catalysis and function of phosphoribosyl-linked serine ubiquitination
Structural and functional investigations demonstrate how bacterial enzymes ubiquitinate host proteins.
- Sissy Kalayil
- , Sagar Bhogaraju
- & Ivan Dikic
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Article |
Structural basis of ubiquitin modification by the Legionella effector SdeA
Crystal structures of the Legionella effector SdeA in a ligand-free state and in complex with ubiquitin and NADH provide insight into SdeA-mediated phosphoribosyl-linked ubiquitination.
- Yanan Dong
- , Yajuan Mu
- & Yue Feng
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Letter |
LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis
The HOIL-1 component of the LUBAC ubiquitin ligase complex is required for LUBAC activity, which prevents lethality during embryogenesis by preventing aberrant TNFR1-mediated endothelial cell death and RIPK1-mediated defects in haematopoiesis.
- Nieves Peltzer
- , Maurice Darding
- & Henning Walczak
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Letter |
Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity
Non-lysine ubiquitination activity of the E3 ubiquitin ligase MYCBP2 is identified by activity-based profiling; biochemical and structural analysis of MYCBP2 suggests the basis for its mechanism and specificity.
- Kuan-Chuan Pao
- , Nicola T. Wood
- & Satpal Virdee
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Letter |
The protein histidine phosphatase LHPP is a tumour suppressor
Decreased expression of histidine phosphatase LHPP, a novel tumour suppressor, results in increased global histidine phosphorylation and hepatocellular carcinoma.
- Sravanth K. Hindupur
- , Marco Colombi
- & Michael N. Hall
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Letter |
Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT
The X-ray structure of the integral membrane protein isoprenylcysteine carboxyl methyltransferase suggests mechanisms by which it recognizes both water-soluble and membrane-bound reactants to catalyze the methylation of RAS and other CAAX proteins at the membrane-cytosol interface.
- Melinda M. Diver
- , Leanne Pedi
- & Stephen B. Long
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Letter |
KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase
The histone acetyl transferase KAT2A (also known as GCN5) can also catalyse histone succinylation, with the α-KGDH complex providing a local source of succinyl-CoA.
- Yugang Wang
- , Yusong R. Guo
- & Zhimin Lu
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Letter |
Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control
The methyltransferase METTL3 promotes the leukaemic state in acute myeloid leukaemia (AML) by catalysing the m6A RNA modification through its recruitment on the transcription start sites of AML-associated genes.
- Isaia Barbieri
- , Konstantinos Tzelepis
- & Tony Kouzarides
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Letter |
Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance
Abundance of PD-L1, the ligand of the anti-cancer immunotherapy target PD-1, is negatively regulated by poly-ubiquitination via the cyclin D–CDK4/cullin 3–SPOP axis and PD-1 blockade treatment in mice improved survival when combined with CDK4/6 inhibitors.
- Jinfang Zhang
- , Xia Bu
- & Wenyi Wei
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Letter |
A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair
A signalling mechanism in human cells for sensing DNA damage induced by alkylation involves ubiquitin-dependent recruitment of the alkylation repair complex ASCC to the vicinity of the damage and co-localization with transcription and splicing factors.
- Joshua R. Brickner
- , Jennifer M. Soll
- & Nima Mosammaparast
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Article |
Structure of PINK1 in complex with its substrate ubiquitin
Stabilization of a transient protein kinase–substrate complex using a nanobody provides molecular details about how the Parkinson’s disease-linked protein kinase PINK1 phosphorylates ubiquitin, and suggests new pharmacological strategies.
- Alexander F. Schubert
- , Christina Gladkova
- & David Komander
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Article |
Molecular basis of USP7 inhibition by selective small-molecule inhibitors
Small molecules are identified that inhibit the ubiquitin-specific protease USP7 with high affinity and specificity as explained by co-crystal structures, and are shown to reduce tumour growth in mice.
- Andrew P. Turnbull
- , Stephanos Ioannidis
- & David Komander
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Letter |
USP7 small-molecule inhibitors interfere with ubiquitin binding
The development of selective ubiquitin-specific protease-7 (USP7) inhibitors GNE-6640 and GNE-6776, which induce tumour cell death and reveal differential kinetics of Lys-48 and Lys-63-linked ubiquitin chain depolymerization by USP7.
- Lorna Kategaya
- , Paola Di Lello
- & Ingrid E. Wertz
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Letter |
Comparative glycoproteomics of stem cells identifies new players in ricin toxicity
A novel quantitative approach to identify intact glycopeptides from comparative proteomic data sets, allowing inference of complex glycan structures and direct mapping of them to sites within the associated proteins at the proteome scale.
- Johannes Stadlmann
- , Jasmin Taubenschmid
- & Josef M. Penninger
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Letter |
ISWI chromatin remodellers sense nucleosome modifications to determine substrate preference
A high-throughput approach using a DNA-barcoded nucleosome library shows that ISWI chromatin remodellers can distinguish between differently modified nucleosomes.
- Geoffrey P. Dann
- , Glen P. Liszczak
- & Tom W. Muir
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Letter |
PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth
PTEN, a known tumour suppressor, inhibits the FXBL2-dependent degradation of IP3R3, an IP3 receptor, thus augmenting IP3R3-mediated calcium release from the endoplasmic reticulum to mitochondria and inducing apoptosis; inhibiting FXBL2 sensitizes PTEN-deficient tumours to photodynamic therapy.
- Shafi Kuchay
- , Carlotta Giorgi
- & Michele Pagano
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Article |
Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory
The metabolic enzyme acetyl coenzyme A synthetase directly regulates gene expression during memory formation by binding to specific genes and providing acetyl coenzyme A for histone acetylation.
- Philipp Mews
- , Greg Donahue
- & Shelley L. Berger
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Letter |
Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne
The structures of the deubiquitinating enzyme Cezanne alone or in complex with its substrate or product are solved, showing how Cezanne specifically targets Lys11-linked polyubiquitin.
- Tycho E. T. Mevissen
- , Yogesh Kulathu
- & David Komander
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Letter |
Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode
The acidic domain of SET binds and represses unacetylated p53, but this interaction is prevented by cellular-stress-induced p53 CTD acetylation.
- Donglai Wang
- , Ning Kon
- & Wei Gu
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Article |
A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase
This paper reports the identification of a new cereblon-modulating agent, CC-885, which targets the translation termination factor GSPT1 and demonstrates anti-tumour activity in patient-derived tumour cells; the crystal structure of the cereblon–DDB1–GSPT1–CC-885 complex reveals a common motif for cereblon-substrate recruitment.
- Mary E. Matyskiela
- , Gang Lu
- & Philip P. Chamberlain
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Article |
Cullin–RING ubiquitin E3 ligase regulation by the COP9 signalosome
Much of the intracellular protein degradation in eukaryotes is controlled by cullin–RING ubiquitin ligases (CRLs), a vast class of enzymes which are regulated by the COP9 signalosome (CSN); structural characterization of CSN–N8CRL4A complexes by cryo-electron microscopy reveals an induced-fit mechanism of CSN activation triggered only by catalytically activated CRLs without bound substrate, explaining how CSN acts as a global regulator of CRLs.
- Simone Cavadini
- , Eric S. Fischer
- & Nicolas H. Thomä
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Letter |
Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase
Thalidomide and its derivative lenalidomide bind the CRL4CRBN E3 ubiquitin ligase and target protein substrates for degradation; structural and functional data determined here show that casein kinase 1α and the lymphoid transcription factor Ikaros, the efficacy targets of lenalidomide in two different blood cancers, interact with the CRBN–lenalidomide interface through a β-hairpin destruction motif.
- Georg Petzold
- , Eric S. Fischer
- & Nicolas H. Thomä
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Letter |
Structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation
The first structure of fully active HOIP of the RBR family of RING-type E3 ligases in its transfer complex with an E2~ubiquitin conjugate provides insights into its mechanism of action, including the ideal alignment of the E2 and E3 catalytic centres for ubiquitin transfer and the allosteric regulation of the RBR family.
- Bernhard C. Lechtenberg
- , Akhil Rajput
- & Stefan J. Riedl
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Article |
SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination
Symmetric dimethylation of the human RNA polymerase II C-terminal domain residue R1810 by the protein arginine methyltransferase 5 (PRMT5) directly recruits the protein survival of motor neuron (SMN) and indirectly recruits the helicase senataxin to resolve R-loops and promote transcription termination.
- Dorothy Yanling Zhao
- , Gerald Gish
- & Jack F. Greenblatt
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Letter |
Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage
At the initiation of DNA double-strand break repair, a number of ubiquitylation events occur; here, the RNF8 ubiquitin E3 ligase and the ubiquitin-conjugating E2 enzyme, UBC13, are shown to primarily modify H1-type linker histones, via a K63 linkage.
- Tina Thorslund
- , Anita Ripplinger
- & Niels Mailand
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Letter |
Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth
Expression of the tumour suppressor PTEN in disseminated primary tumour cells is lost after tumour cells metastasize to the brain, with downregulation instigated by microRNAs from astrocytes, which are transferred from cell to cell by exosomes; these findings reveal the dynamic nature of metastatic cancer cells when adapting to a new tissue environment.
- Lin Zhang
- , Siyuan Zhang
- & Dihua Yu
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Letter |
Cell-fate determination by ubiquitin-dependent regulation of translation
This study shows that a vertebrate-specific ubiquitin ligase modulates neural crest specification in Xenopus development and human embryonic stem-cell differentiation; a proteomics approach reveals that the CUL3KBTBD8 ligase modulates translation by targeting the modulators of ribosomes production NOLC1 and its paralogue TCOF1, which is mutated in a neural-crest-associated syndrome.
- Achim Werner
- , Shintaro Iwasaki
- & Michael Rape
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Article |
Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth
A ChIP-seq analysis of the DNA-binding properties of mutant gain-of-function p53 protein compared to wild-type p53 reveals the gain-of-function proteins bind to and activate a distinct set of genes including chromatin modifying enzymes such as the histone methyltransferase MLL; small molecular inhibitors of MLL function may represent a new target for cancers with mutant p53.
- Jiajun Zhu
- , Morgan A. Sammons
- & Shelley L. Berger
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Article |
The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy
The PINK1 ubiquitin kinase is shown to recruit the two autophagy receptors NDP52 and OPTN to mitochondria to activate mitophagy directly, independently of the ubiquitin ligase parkin; once recruited to mitochondria, NDP52 and OPTN recruit autophagy initiation components, and parkin may amplify the phospho-ubiquitin signal generated by PINK1, resulting in robust autophagy induction.
- Michael Lazarou
- , Danielle A. Sliter
- & Richard J. Youle
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Letter |
Mechanism of phospho-ubiquitin-induced PARKIN activation
This study provides insights into conformational changes that lead to phospho-ubiquitin-induced PARKIN activation and how PARKIN is recruited to phospho-ubiquitin chains on mitochondria; the crystal structure of PARKIN in complex with phospho-ubiquitin also indicates that the pocket within PARKIN where phospho-ubiquitin binds carries amino acid residues that are mutated in patients with autosomal-recessive juvenile Parkinsonism.
- Tobias Wauer
- , Michal Simicek
- & David Komander
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Article |
Atomic structure of the APC/C and its mechanism of protein ubiquitination
A cryo-electron microscopy determination of the atomic structures of anaphase-promoting complex (APC/C)–coactivator complexes with either Emi1 or a UbcH10–ubiquitin conjugate.
- Leifu Chang
- , Ziguo Zhang
- & David Barford
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Letter |
Allosteric activation of the RNF146 ubiquitin ligase by a poly(ADP-ribosyl)ation signal
Structural and biochemical approaches are used to show how RNF146 activity is allosterically regulated by the binding of poly(ADP-ribose) ligand, and how substrate specificity is achieved with protein poly(ADP-ribosyl)ation and ubiquitination occurring in the same protein complex.
- Paul A. DaRosa
- , Zhizhi Wang
- & Wenqing Xu
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Letter |
Regulation of RNA polymerase II activation by histone acetylation in single living cells
The interplay of histone acetylation and RNA polymerase II activity is investigated using fluorescence microscopy; acetylation of H3 at Lys 27 enhances the recruitment of a transcriptional activator and accelerates the transition of RNA polymerase II from initiation to elongation, thus indicating that histone acetylation has a causal effect on two distinct steps in transcription activation.
- Timothy J. Stasevich
- , Yoko Hayashi-Takanaka
- & Hiroshi Kimura
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Letter |
SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer
SMYD3 is a methyltransferase overexpressed in several human tumours; here methylation of the MAP3K2 kinase by SMYD3 is shown to be critical for Ras-induced tumour development in mouse models and human tumour cells, showing an unexpected role for methylation in a kinase signalling pathway and revealing a candidate therapeutic target.
- Pawel K. Mazur
- , Nicolas Reynoird
- & Or Gozani
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Letter |
Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus
Phosphorylation of Akt at its carboxy-terminal tail is an essential layer of Akt activation to regulate its physiological functions.
- Pengda Liu
- , Michael Begley
- & Wenyi Wei
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Letter |
Structural basis for ubiquitin-mediated antiviral signal activation by RIG-I
RIG-I protein recognizes viral duplex RNA with a 5′-triphosphate group, activating innate immune responses; a crystal structure of its tetrameric CARD signalling domain reveals that non-covalently linked ubiquitin chains stabilize the tetramer in a ‘lock-washer’ structure that serves as a signalling platform for the recruitment and activation of MAVS.
- Alys Peisley
- , Bin Wu
- & Sun Hur
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Letter |
LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy
This study finds a direct correlation between LARGE-glycan extension on dystroglycan and the protein’s capacity for extracellular matrix ligands; in regenerating mouse muscle, short LARGE-glycan polysaccharides cause various defects, including muscle dysfunction and a predisposition to dystrophy, and in muscular dystrophy patients, increased clinical severity of disease corresponds to shorter LARGE-glycans.
- Matthew M. Goddeeris
- , Biming Wu
- & Kevin P. Campbell
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Letter |
Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation
CaMKII is known to be pathologically activated in heart failure and arrhythmias; here it is shown that glucose-induced CaMKII activation via O-linked glycosylation might contribute to cardiac pathology in diabetes.
- Jeffrey R. Erickson
- , Laetitia Pereira
- & Donald M. Bers
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Letter |
Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains
Several death-domain-containing proteins are directly inactivated by the enteropathogenic Escherichia coli type III secretion system effector NleB; NleB functions as an N-acetylglucosamine transferase that modifies a conserved death domain arginine residue, blocking the receptor–adapter interaction.
- Shan Li
- , Li Zhang
- & Feng Shao
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Letter |
The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy
Induction of autophagy is coupled to reduction of histone H4 lysine 16 acetylation through downregulation of the histone acetyltransferase hMOF, showing that histone modifications regulate the outcome of autophagy.
- Jens Füllgrabe
- , Melinda A. Lynch-Day
- & Bertrand Joseph
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Article |
Temporal regulation of EGF signalling networks by the scaffold protein Shc1
The Shc1 scaffold mediates a switch in the signaling output of the epidermal growth factor receptor tyrosine kinase over time through recruitment of successive waves of proteins with distinct biological functions.
- Yong Zheng
- , Cunjie Zhang
- & Tony Pawson
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Article |
53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark
This study shows that 53BP1 recruitment to sites of DNA damage involves dual recognition of H4K20me2 and H2AK15 histone ubiquitination; the ubiquitin mark and the surrounding epitope on H2A are read by a region of 53BP1 designated the ubiquitination-dependent recruitment motif.
- Amélie Fradet-Turcotte
- , Marella D. Canny
- & Daniel Durocher
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News & Views |
Death by deacetylation
Necrosis is associated with various diseases, yet it is arguably the least-understood form of programmed cell death. It emerges that a sirtuin protein regulates one form of necrosis through a deacetylation reaction. See Article p.199
- Wen Zhou
- & Junying Yuan
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Article |
The NAD-dependent deacetylase SIRT2 is required for programmed necrosis
Here it is shown that the NAD-dependent deacetylase SIRT2 is an essential component of necrosis, and that mouse hearts that do not contain SIRT2 or that are treated with a pharmacological inhibitor of SIRT2 are largely protected from ischaemic injury.
- Nisha Narayan
- , In Hye Lee
- & Toren Finkel
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Article |
Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq
N6-methyladenosine (m6A) is the most prevalent internal modification in messenger RNA; here the human and mouse m6A modification landscape is presented in a transcriptome-wide manner, providing insights into this epigenetic modification.
- Dan Dominissini
- , Sharon Moshitch-Moshkovitz
- & Gideon Rechavi