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The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis
E3 ligases that attach ubiquitin to proteins destined for proteasomal degradation are regulated by neddylation. In this study, Xie et al. show that the HECT ligase Smurf1, which is a ubiquitin ligase, is also neddylated, and this post-translational modification enhances its ligase activity.
- Ping Xie
- , Minghua Zhang
- & Lingqiang Zhang
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| Open AccessA high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation
The human cytomegalovirus protein US11 downregulates host immune responses by redirecting HLA class I molecules for endoplasmic reticulum-associated protein degradation. Using a high-coverage genome-wide shRNA screen, the authors identify TMEM129 as an E3 ubiquitin ligase essential for this process.
- Michael L. van de Weijer
- , Michael C. Bassik
- & Robert Jan Lebbink
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Emi2 mediates meiotic MII arrest by competitively inhibiting the binding of Ube2S to the APC/C
In vertebrates, unfertilized eggs arrest at metaphase of meiosis II via Emi2, which inhibits APC/C ubiquitin ligase. Here, Sako et al.show that on fertilization the degradation of Emi2 allows binding between APC/C and the C-terminal tail of the ubiquitin-conjugating enzyme Ube2S, thus releasing the meiotic arrest.
- Kosuke Sako
- , Kazuhiro Suzuki
- & Noriyuki Sagata
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Sensitive detection of proteasomal activation using the Deg-On mammalian synthetic gene circuit
Proteasome activity can be monitored using a fluorescent substrate; however, screening for proteasome activators using this technique is challenging as signal loss is intrinsically more difficult to detect. Zhao et al.design a genetic inverter circuit that reports increased proteasome activity as signal gain.
- Wenting Zhao
- , Matthew Bonem
- & Laura Segatori
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The 19S proteasome subunit Rpt3 regulates distribution of CENP-A by associating with centromeric chromatin
The histone variant CENP-A has a crucial role in defining centromeric chromatin and is required for accurate segregation of chromosomes during mitosis. Here, Kitagawa et al.identify Rpt3, a subunit of the 19S proteasome, as a novel factor regulating CENP localization.
- Teppei Kitagawa
- , Kojiro Ishii
- & Tomohiro Matsumoto
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| Open AccessA DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect
Defective proteins or functional proteins that are no longer needed can be degraded in the endoplasmic reticulum. In this study, Lopez-Serra et al.show that DERL3, which is involved in protein degradation in the endoplasmic reticulum, is aberrantly silenced in cancer, leading to activation of a glucose transporter and dysregulated glycolysis.
- Paula Lopez-Serra
- , Miguel Marcilla
- & Manel Esteller
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| Open AccessHACE1-dependent protein degradation provides cardiac protection in response to haemodynamic stress
HACE1 is an E3 ubiquitin ligase known to regulate various cell biological processes. Here, Zhang et al.identify HACE1 as a protective factor in the heart, demonstrating that HACE1 inhibits the development of heart failure in response to haemodynamic stress by regulating protein degradation pathways.
- Liyong Zhang
- , Xin Chen
- & Peter P. Liu
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Quantitative live-cell imaging reveals spatio-temporal dynamics and cytoplasmic assembly of the 26S proteasome
The 26S proteasome is assembled in several steps, however the extent to which this assembly occurs before or after transport into the nucleus remains unclear. Pack et al.show that full assembly can occur in the cytoplasm, and that a concatameric form of the fully assembled complex is a substrate for nuclear import.
- Chan-Gi Pack
- , Haruka Yukii
- & Yasushi Saeki
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| Open AccessPlant cysteine oxidases control the oxygen-dependent branch of the N-end-rule pathway
Oxygen sensing in plants is mediated by the N-end rule pathway, in which the N-terminal cysteine residue of ERF-VII transcription factors is selectively oxidised. Weits et al.identify cysteine oxidases responsible for this modification, and show that their expression is itself regulated by ERF-VII.
- Daan A. Weits
- , Beatrice Giuntoli
- & Francesco Licausi
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Trunk cleavage is essential for Drosophila terminal patterning and can occur independently of Torso-like
Terminal patterning of the Drosophila embryo is thought to be regulated by local cleavage of the ubiquitous peptide hormone Trunk (Trk) controlled by the maternal gene torso-like (tsl)that is expressed only at embryo poles. Here, the authors show that cleavage of Trk is indeed required for patterning and can occur independently of Tsl.
- Michelle A. Henstridge
- , Travis K. Johnson
- & James C. Whisstock
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| Open AccessActivation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation
The NLRP1b inflammasome activation may lead to pyroptosis and secretion of the inflammatory cytokines IL-1ß and IL-18 but the mechanisms behind these processes are not fully understood. Here, the authors show that they can occur independently of the inflammasome adaptor ASC and without caspase-1 autoprocessing.
- Nina Van Opdenbosch
- , Prajwal Gurung
- & Mohamed Lamkanfi
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A molecular brake controls the magnitude of long-term potentiation
Suprachiasmatic nucleus circadian oscillatory protein (SCOP) is implicated in long-term potentiation. Here, the authors show that μ-calpain-mediated SCOP degradation contributes to long-term potentiation induction, whereas m-calpain-mediated stimulation of SCOP synthesis restricts long-term potentiation.
- Yubin Wang
- , Guoqi Zhu
- & Michel Baudry
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Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination
The long non-coding RNA HOTAIR acts as a scaffold to bring together chromatin silencing complexes in the nucleus. Here, the authors show that HOTAIRalso serves as a scaffold between E3 ubiquitin ligases and their substrates and thereby enhances their ubiquitination.
- Je-Hyun Yoon
- , Kotb Abdelmohsen
- & Myriam Gorospe
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The APC/C cofactor Cdh1 prevents replicative stress and p53-dependent cell death in neural progenitors
The E3-ubiquitin ligase APC/C and its cofactor Cdh1 have been shown to play important roles in axonal growth and synaptic plasticity. In this study, Eguren et al.show that elimination of Cdh1 in the developing nervous system results in defects in the neural progenitor compartment, hydrocephalus and reduced lifespan.
- Manuel Eguren
- , Eva Porlan
- & Marcos Malumbres
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APC/C-Cdh1 coordinates neurogenesis and cortical size during development
The E3 ubiquitin ligase APC/C plays a critical role in cell cycle progression. In this study, Delgado-Esteban et al. show that APC/C bound to the co-factor Cdh1 is necessary for neural progenitor cell maintenance and neuronal differentiation.
- Maria Delgado-Esteban
- , Irene García-Higuera
- & Angeles Almeida
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Proteasomal degradation of Nck1 but not Nck2 regulates RhoA activation and actin dynamics
Nck1/2 adaptor proteins control the assembly and activity of protein complexes that promote actin polymerization. Buvall et al.show that Nck1 abundance is regulated by the E3 ubiquitin ligase c-Cbl, which competes for Nck binding with the actin-binding protein synaptopodin in podocytes.
- Lisa Buvall
- , Priyanka Rashmi
- & Peter Mundel
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| Open AccessStructural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin
R-spondins are secreted factors that potentiate Wnt signalling by inhibiting the degradation of Wnt receptors by transmembrane E3 ubiquitin ligases. Zebisch et al.present a panel of crystal structures that reveal how this inhibition occurs.
- Matthias Zebisch
- , Yang Xu
- & E. Yvonne Jones
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| Open AccessDifferential regulation of the REGγ–proteasome pathway by p53/TGF-β signalling and mutant p53 in cancer cells
REGγ is a proteasome activator and is frequently overexpressed in cancer cells. Here Ali et al. demonstrate that p53/TGF-β signalling inhibits REGγ expression, whereas p53 mutations increase REGγ transcription, identifying a gain of function for mutant p53.
- Amjad Ali
- , Zhuo Wang
- & Xiaotao Li
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Smurf2 suppresses B-cell proliferation and lymphomagenesis by mediating ubiquitination and degradation of YY1
Mice deficient in the E3 ubiquitin ligase Smurf2 spontaneously develop B-cell lymphomas. Here Ramkumar et al.show that Smurf2 regulates B-cell proliferation by ubiquitinating the transcription factor YY1, and that Smurf2 expression correlates negatively with survival of patients with diffuse large B-cell lymphoma.
- Charusheila Ramkumar
- , Hang Cui
- & Hong Zhang
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Pellino3 targets RIP1 and regulates the pro-apoptotic effects of TNF-α
Pellino family proteins are ubiquitin ligases known to regulate immune signalling. Here Yang et al. show that Pellino3 regulates apoptotic TNF signalling by modulating the composition of the death-induced signalling complex, and that absence of Pellino3 sensitizes mice to TNF.
- Shuo Yang
- , Bingwei Wang
- & Paul N. Moynagh
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| Open AccessOTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3
TGFβ signalling through SMAD proteins controls many different processes, both during embryonic development and in adult tissues. Herhaus et al. show that the deubiquitinase OTUB1 promotes TGFβ signalling by binding specifically to activated SMAD2/3 complexes and inhibiting their ubiquitiylation.
- Lina Herhaus
- , Mazin Al-Salihi
- & Gopal P. Sapkota
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Inflammation-induced proteolytic processing of the SIRPα cytoplasmic ITIM in neutrophils propagates a proinflammatory state
SIRPα is an anti-inflammatory signalling receptor expressed on neutrophils. Here Zenet al.show that during inflammation, SIRPα signalling is inhibited by cleavage of its intracellular signalling motif.
- Ke Zen
- , Yalan Guo
- & Yuan Liu
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MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling
The protein MG53 is known to inhibit myogenesis. Here, Ko et al. show that MG53 is an E3 ubiquitin ligase that mediates degradation of insulin receptor substrate 1 in skeletal muscle, thereby regulating myogenesis and insulin sensitivity in vitro and in vivo.
- Jae-Sung Yi
- , Jun Sub Park
- & Young-Gyu Ko
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Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production
Clinical trials of γ-secretase inhibitors to treat Alzheimer’s disease show that side effects occur from their non-selective action. Dimitrov et al.show that improved second generation γ-secretase modulators spare cleavage sites of substrate proteins that are implicated in the side effects.
- Mitko Dimitrov
- , Jean-René Alattia
- & Patrick C. Fraering
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Involvement of Bag6 and the TRC pathway in proteasome assembly
The 26S proteasome comprises over 33 different subunits that must be correctly assembled by dedicated chaperones for efficient protein degradation. Here the authors find that general chaperone proteins are also vital for proper proteasome assembly.
- Takashi Akahane
- , Kazutaka Sahara
- & Shigeo Murata
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| Open AccessStructure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases
The Parkinson’s disease-associated protein Parkin regulates the fate of damaged mitochondria by ubiquitinating mitochondrial substrates. Riley et al. present the crystal structure of the Parkin-R0RBR domain, providing new insight into the catalytic mechanism of the enzyme.
- B.E. Riley
- , J.C. Lougheed
- & J.A. Johnston
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| Open AccessProteolysis of MOB1 by the ubiquitin ligase praja2 attenuates Hippo signalling and supports glioblastoma growth
Tumour suppressors can be inactivated in cancer not only as a result of mutation, but also by proteolytic degradation. Here the authors show that, during glioma development, the accumulation of the ubiquitin ligase praja2 sustains tumour growth by degrading MOB1—a core component of the Hippo pathway.
- Luca Lignitto
- , Antonietta Arcella
- & Antonio Feliciello
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| Open AccessCSN- and CAND1-dependent remodelling of the budding yeast SCF complex
CAND1 promotes the activity of Cullin–RING ubiquitin ligases, but binds exclusively to inactive unneddylated forms of the enzyme. By identifying a simple means to reversibly activate this complex in budding yeast, Zemla et al. resolve this paradox and show that CAND1 acts as an exchange factor for substrate adaptors.
- Aleksandra Zemla
- , Yann Thomas
- & Thimo Kurz
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CAND1 controls in vivo dynamics of the cullin 1-RING ubiquitin ligase repertoire
Cullin 1-RING ubiquitin ligase complexes interact with a wide variety of substrates by recruiting different substrate receptor subunits. Here the authors demonstrate that CAND1 promotes rapid exchange of substrate receptors, thus ensuring comprehensive sampling of the entire repertoire.
- Shuangding Wu
- , Wenhong Zhu
- & Dieter A. Wolf
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| Open AccessReversible inactivation of deubiquitinases by reactive oxygen species in vitro and in cells
Deubiquitinases regulate protein stability, localization and activity, and yet the mechanisms controlling their activity remain poorly understood. Lee et al. show that these enzymes are reversibly inhibited by reactive oxygen species through oxidation of catalytic cysteine residues.
- Jin-Gu Lee
- , Kheewoong Baek
- & Yihong Ye
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Regulation of A20 and other OTU deubiquitinases by reversible oxidation
Ovarian tumour deubiquitinases are cysteine proteases that cleave polyubiquitin chains. Here the authors show that these enzymes are susceptible to reversible oxidation, and present crystal structures which reveal how the reversibly oxidized catalytic cysteine residue is stabilized by the active site.
- Yogesh Kulathu
- , Francisco J. Garcia
- & David Komander
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Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase
The proapoptotic protein Siva1 has been shown to inhibit the tumour suppressor p53, however, it remains unclear how this activity is mediated. Here the authors show that Siva1 is an E3 ubiquitin ligase which inhibits p53 by promoting the degradation of ARF.
- Xingwu Wang
- , Meng Zha
- & Mian Wu
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Arabidopsis ubiquitin ligase MIEL1 mediates degradation of the transcription factor MYB30 weakening plant defence
In plants, the regulatory mechanisms that control disease resistance responses remain poorly understood. Marino et al. show that the Arabidopsis E3 ubiquitin ligase MIEL1 interacts with and ubiquitinates the MYB transcription factor (TF), MYB30, leading to proteasomal degradation of MYB30 and attenuation of plant defence.
- Daniel Marino
- , Solène Froidure
- & Susana Rivas
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Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Aβ toxicity in Drosophila
PAR-1 inDrosophilahas been identified as a key physiological tau kinase. Lee and colleagues perform genetic screens for regulators of PAR-1 and find that it is targeted for ubiquitination and degradation by the ubiquitin ligase complex SCF(Slimb), and that this pathway modulates synaptic morphology.
- Seongsoo Lee
- , Ji-Wu Wang
- & Bingwei Lu
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PPARγ is an E3 ligase that induces the degradation of NFκB/p65
NFκB/p65 and PPARγ are both transcription factors that perform distinct but overlapping roles in cellular regulation. Hou et al. report that PPARγ acts as an E3 ubiquitin ligase and promotes Lys48-linked ubiquitination and degradation of p65, terminating NFκB-mediated inflammation and tumorigenesis.
- Yongzhong Hou
- , France Moreau
- & Kris Chadee
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Cellulose degradation and assimilation by the unicellular phototrophic eukaryote Chlamydomonas reinhardtii
Although cellulose is abundant in the biosphere, its potential as a source of biofuel depends on finding efficient ways to degrade it. Blifernez-Klassen et al. show that phototrophic microalga Chlamydomonas reinhardtiican metabolize cellulose, indicating its potential as a catalyst for biofuel production.
- Olga Blifernez-Klassen
- , Viktor Klassen
- & Olaf Kruse
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p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO
The IKK complex activates the NF-κB pathway and can culminate in inflammation, which needs to be tightly controlled. NEMO is part of the IKK complex and, in this study, is shown to associate with the golgi-reassembly protein p47, resulting in the lysosomal degradation of NEMO and inhibition of NF-κB activation.
- Yuri Shibata
- , Masaaki Oyama
- & Jun-ichiro Inoue
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| Open AccessProteomic screen reveals Fbw7 as a modulator of the NF-κB pathway
Fbw7 is a ubiquitin-ligase, which targets several oncoproteins for proteolysis, and is therefore important for the control and prevention of tumorigenesis. In this study, Arabi and colleagues carry out a proteomic screen of the targets of Fbw7, and identify Nuclear Factor of κ-B2 as a substrate.
- Azadeh Arabi
- , Karim Ullah
- & Olle Sangfelt
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Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis
Fas-associated protein with death domain (FADD) is part of a signalling complex that controls some forms of programmed cell death. Lee and colleagues demonstrate that FADD ubiquitination by the E3 ubiquitin ligase MKRN1 regulates FADD protein stability and thereby cell death.
- Eun-Woo Lee
- , Jung-Hoon Kim
- & Jaewhan Song
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FAT10 and NUB1L bind to the VWA domain of Rpn10 and Rpn1 to enable proteasome-mediated proteolysis
FAT-10 targets proteins for degradation in a ubiquitin-independent manner and NUB1L accelerates this process. In this study, both FAT-10 and NUB1L are shown to interact with the VWA domain of the Rpn10 subunit of the 26S proteasome, suggesting that this is a receptor site for ubiquitin-like modifiers.
- Neha Rani
- , Annette Aichem
- & Marcus Groettrup
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The ubiquitin ligase HACE1 regulates Golgi membrane dynamics during the cell cycle
The Golgi membrane is fragmented during mitosis and is subsequently fused following cell division and this process is known to be controlled by ubiquitination. In this study, the ubiquitin ligase HACE1 is shown to be targeted to the Golgi membrane and is required for fusion after the completion of mitosis.
- Danming Tang
- , Yi Xiang
- & Yanzhuang Wang
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Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling
Transforming growth factor-β blocks the activation of pro-inflammatory cytokines, in part by the degradation of Myd88. This study shows that smad ubiquitin regulator proteins are shown to mediate the destruction of Myd8 and are therefore required for the anti-inflammatory effects of transforming growth factor-β.
- Youn Sook Lee
- , Jin Seok Park
- & Seok Hee Park
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Regulation of MITF stability by the USP13 deubiquitinase
MITF is a transcription factor required for melanocyte development, which is activated in some melanomas. Zhao and colleagues show that USP13 removes ubiquitin from MITF, stabilizes MITF protein levels and enhances colony formation, suggesting that USP13 may be a therapeutic target in melanoma.
- Xiansi Zhao
- , Brian Fiske
- & David E Fisher
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TorsinA participates in endoplasmic reticulum-associated degradation
The torsinA protein localizes to the endoplasmic reticulum and, when mutated, causes early onset torsion dystonia. The authors reveal a new role for torsinA in proteosome-mediated degradation of misfolded proteins, and relate this to endoplasmic reticulum stress, in aCaenorhabditis elegansmodel and patient fibroblasts.
- Flávia C. Nery
- , Ioanna A. Armata
- & Xandra O. Breakefield
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A photoconvertible fluorescent reporter to track chaperone-mediated autophagy
Soluble cytosolic proteins can be degraded in lysosomes by chaperone-mediated autophagy, however, the current method to measure this process requires isolation of lysosomes. Now, a fluorescent reporter is described that can measure this type of autophagy in intact cells.
- Hiroshi Koga
- , Marta Martinez-Vicente
- & Ana Maria Cuervo
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| Open AccessTRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer
TGFβ can function as both a tumour suppressor and tumour promoter under different cellular contexts. Here, the cleavage product of the TGFβ type I receptor is shown to be generated in a TGFβ-dependent manner, and can induce the expression of genes involved in tumour cell invasion.
- Yabing Mu
- , Reshma Sundar
- & Marene Landström
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| Open AccessRespiratory distress and perinatal lethality in Nedd4-2-deficient mice
In vitrostudies have suggested that the ubiquitin ligase, Nedd4-2, regulates several proteins, including the epithelial sodium channel. Here by examining Nedd4-2-deficient mice, the authors demonstrate that Nedd4-2 is essential for epithelial sodium channel regulation, fetal and postnatal lung function and animal survival.
- Natasha A. Boase
- , Grigori Y. Rychkov
- & Sharad Kumar
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| Open AccessThe deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility
Deubiquitinating enzymes are involved in multiple cellular processes, including cell viability. The authors reveal a role for the deubiquitinating enzyme, USP17, in the migration of cells in response to chemokines and show that USP17 is required for the relocalization of GTPases involved in cell motility.
- Michelle de la Vega
- , Alyson A. Kelvin
- & James A. Johnston
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| Open AccessCSN-mediated deneddylation differentially modulates Ci155 proteolysis to promote Hedgehog signalling responses
Hedgehog signalling gradients are required for proper wing formation inDrosophila, and Hedgehog is known to regulate the cubitus interruptus transcription factor. Here, the authors show that the COP9 signalosome has a critical role in translating a Hedgehog gradient into a cubitus interruptus gradient.
- June-Tai Wu
- , Wei-Hsiang Lin
- & Cheng-Ting Chien