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| Open AccessUbiquitination of stalled ribosome triggers ribosome-associated quality control
Several protein quality control mechanisms are in place to trigger the rapid degradation of aberrant polypeptides and mRNAs. Here the authors describe a mechanism of ribosome-mediated quality control that involves the ubiquitination of ribosomal proteins by the E3 ubiquitin ligase Hel2/RQT1.
- Yoshitaka Matsuo
- , Ken Ikeuchi
- & Toshifumi Inada
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Article
| Open Accessp62/SQSTM1/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis
Soluble misfolded proteins that fail to be degraded by the ubiquitin proteasome system (UPS) are redirected to autophagy via specific adaptors, such as p62. Here the authors show that p62 recognises N-degrons in these proteins, acting as a N-recognin from the proteolytic N-end rule pathway, and targets these cargos to autophagosomal degradation.
- Hyunjoo Cha-Molstad
- , Ji Eun Yu
- & Bo Yeon Kim
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Article
| Open AccessVariation in auxin sensing guides AUX/IAA transcriptional repressor ubiquitylation and destruction
The phytohormone auxin is sensed by SCFTIR1-AUX/IAA receptors leading to AUX/IAA repressor ubiquitylation and turnover. Here the authors show that IAA6 and IAA19 differ in their ubiquitylation and turnover dynamics, differentially contributing to auxin sensing and enabling discrimination of auxin concentrations.
- Martin Winkler
- , Michael Niemeyer
- & Luz Irina A. Calderón Villalobos
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Article
| Open AccessNEDD4 controls spermatogonial stem cell homeostasis and stress response by regulating messenger ribonucleoprotein complexes
Stress granules (SG) comprise aggregates of cellular messenger ribonucleoproteins (mRNPs) but how they form is unclear. Here, the authors identify NEDD4, an E3 ubiquitin ligase, as regulating the RNA binding protein NANOS2 and turnover of mRNP components, and so SG disassembly in spermatogonial stem cells.
- Zhi Zhou
- , Hiroshi Kawabe
- & Yumiko Saga
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Article
| Open AccessLong-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs
The proteasome regulates several important cellular processes and has been identified as a target for therapeutic interventions. Here the authors map the conformational and energy landscape of the 26S proteasome upon Oprozomib binding and uncover long-range allosteric effects that control the dynamic behaviour of the proteasome.
- David Haselbach
- , Jil Schrader
- & Holger Stark
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Article
| Open AccessUfd2p synthesizes branched ubiquitin chains to promote the degradation of substrates modified with atypical chains
How ubiquitination affects the proteins it modifies varies according to the type of linkage between ubiquitin moieties. Here, Liuet al. show how yeast Udf2p promotes K48 linkage formation onto K29-linked chains to generate branched K29-K48 ubiquitin chains that target its substrate to the proteasome.
- Chao Liu
- , Weixiao Liu
- & Wei Li
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Article
| Open AccessThe β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor
F-box proteins β-TrCP1 and SKP2 act as oncogenes by promoting targeted degradation of critical protein substrates. Here, the authors identify an axis of F-box proteins β-TrCP1-FBXW2-SKP2 where FBXW2 is a substrate of β-TrCP1 but mediates the degradation of SKP2, thus acting as a tumour suppressor.
- Jie Xu
- , Weihua Zhou
- & Yi Sun
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Article
| Open AccessStructural basis for the recognition and degradation of host TRIM proteins by Salmonella effector SopA
The HECT-like E3 ligase SopA inSalmonellahas been suggested to activate host RING ligases TRIM56 and TRIM65. Here, the authors use mass spectrometry, crystal structures and biochemistry to examine the interactions between these proteins in detail.
- Evgenij Fiskin
- , Sagar Bhogaraju
- & Ivan Dikic
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Article
| Open AccessCCT complex restricts neuropathogenic protein aggregation via autophagy
The CCT complex, a key player in the chaperone machinery, has been implicated in Huntington’s disease. Pavelet al. show that CCT2/5/7 also play an essential role in autophagosome degradation, and that the aggregation of proteins upon CCT2/5/7 depletion is primarily a consequence of impaired autophagy.
- Mariana Pavel
- , Sara Imarisio
- & David C. Rubinsztein
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Article
| Open AccessThe Nedd4-2/Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation
Aberrant activation of the IgE receptor on mast cells leads to allergic responses. Here, the authors identify an E3 ligase and adaptor protein that can reduce IgE signalling by targeting phosphorylated-Syk for degradation.
- Kwok Ho Yip
- , Natasha Kolesnikoff
- & Michele A. Grimbaldeston
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Article
| Open AccessQuantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers
The AAA+ ATPase p97 is an essential hexameric protein with multiple protein interaction partners and cellular functions. Here, the authors use interaction mapping to examine partner proteins of this large complex, and assess the effects of these proteins on the disassembly of the p97 complex.
- Anup Arumughan
- , Yvette Roske
- & Erich E. Wanker
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Article
| Open AccessBimodal antagonism of PKA signalling by ARHGAP36
Protein kinase A (PKA) is a key mediator of cyclic AMP signalling. Here, Eccles et al. show that ARHGAP36 antagonizes PKA by acting as a kinase inhibitor and targeting the catalytic subunit for endolysosomal degradation, thus reducing sensitivity of cells to cAMP and promoting Hedgehog signalling.
- Rebecca L. Eccles
- , Maciej T. Czajkowski
- & Oliver Rocks
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Article
| Open AccessDeubiquitinase activity is required for the proteasomal degradation of misfolded cytosolic proteins upon heat-stress
Ubiquitination of misfolded proteins usually results in protein degradation. Here, the authors show that two deubiquitinases—enzymes that remove ubiquitin—are required for the proteasomal degradation of misfolded proteins in response to heat-shock in yeast.
- Nancy N. Fang
- , Mang Zhu
- & Thibault Mayor
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Article
| Open AccessStructure of ubiquitylated-Rpn10 provides insight into its autoregulation mechanism
Ubiquitin (Ub) receptors are responsible for the recognition of ubiquitylated proteins. Here the authors describe the crystal structure of the ubiquitylated form of the Ub-receptor Rpn10, which suggest that ubiquitylation of Rpn10 promotes its dissociation from the proteasome.
- Tal Keren-Kaplan
- , Lee Zeev Peters
- & Gali Prag
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Article
| Open AccessCullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection
CtIP has a key role in DNA double-strand break repair as its role in resecting DNA at the break commits a cell to homologous recombination. Here the authors show that KLHL15 interacts with CtIP and regulates repair by controlling protein turnover.
- Lorenza P. Ferretti
- , Sarah-Felicitas Himmels
- & Alessandro A. Sartori
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Article
| Open AccessPhenotypes on demand via switchable target protein degradation in multicellular organisms
Switching target protein accumulation and activity by portable conditional degrons is potentially useful for both basic research and bioengineering. Here the authors present a versatile system to tune protein levels in live animals and plants using a temperature-sensitive N-end rule degradation signal.
- Frederik Faden
- , Thomas Ramezani
- & Nico Dissmeyer
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Article
| Open AccessThe ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity
Hrd1 is an E3 ubiquitin ligase involved in ER-associated degradation and MHC I turnover. Here the authors use T-cell-specific ko mice and a mouse model of multiple sclerosis to show that Hrd1 also drives pro-inflammatory T helper cell responses and contributes to pathogenesis of autoimmune disease.
- Yuanming Xu
- , Fang Zhao
- & Deyu Fang
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Article
| Open AccessCritical role of RanBP2-mediated SUMOylation of Small Heterodimer Partner in maintaining bile acid homeostasis
As signalling molecules, bile acids (BAs) can affect metabolism, but due to detergent-like properties, BA levels must be tightly regulated. Here, Kim et al.show that RanBP2, a nucleoporin, maintains BA homoeostasis through SUMOylation of Small Heterodimer Partner (SHP), an orphan nuclear receptor.
- Dong-Hyun Kim
- , Sanghoon Kwon
- & Jongsook Kim Kemper
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Article
| Open AccessThe FANCD2–FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2
FANCD2 and FANCI are essential components of the Fanconi anaemia DNA damage repair pathway. Here the authors present the cryo-EM structure of the FANCD2-FANCI complex, providing insight into how the complex is recruited to stalled replication forks.
- Chih-Chao Liang
- , Zhuolun Li
- & Martin A. Cohn
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Article
| Open AccessNEDDylation promotes stress granule assembly
Stress granules that form in response to stress contain translationally stalled mRNPs and play important roles in cellular homeostasis. Here the authors implicate SRSF3 neddylation as an important factor in the formation of stress granules in response to arsenite exposure.
- Aravinth Kumar Jayabalan
- , Anthony Sanchez
- & Takbum Ohn
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Article
| Open AccessMBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta
Osteogenesis imperfecta (OI) is genetically linked to autosomal dominant or autosomal recessive mutations. Here, Marini et al. describe two families with X-chromosome-linked OI with mutations in MBTPS2 that alter regulated intramembrane proteolysis and subsequent defects in collagen crosslinking and osteoblast function.
- Uschi Lindert
- , Wayne A. Cabral
- & Vorasuk Shotelersuk
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Article
| Open AccessA neomorphic cancer cell-specific role of MAGE-A4 in trans-lesion synthesis
RAD18 is an important protein in trans-lesion synthesis, an error-prone damage-tolerant mode of DNA replication. Here the authors show that MAGE-A4 stabilizes RAD18 and allows cancer cells to maintain on-going DNA synthesis in the face of genotoxic injury.
- Yanzhe Gao
- , Elizabeth Mutter-Rottmayer
- & Cyrus Vaziri
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Article
| Open AccessLong noncoding RNA NRON contributes to HIV-1 latency by specifically inducing tat protein degradation
Long noncoding RNAs have a wide range of physiological functions, though their role in viral infection and latency is poorly understood. Here the authors show a lncRNA NRON can induce degradation of HIV-1 protein Tat, potentially contributing to latent infection.
- Jun Li
- , Cancan Chen
- & Hui Zhang
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Article
| Open AccessGenetic dissection of mammalian ERAD through comparative haploid and CRISPR forward genetic screens
CRISPR/Cas9-mediated forward genetic screens and gene-trap mutagenesis screens in haploid cells are both powerful techniques to examine gene function. Here, the authors show the two approaches have high concordance and identify an uncharacterized gene, TXNDC11, which is involved in endoplasmic reticulum-associated degradation.
- Richard T. Timms
- , Sam A. Menzies
- & Paul J. Lehner
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Article
| Open AccessSyndecan-4 negatively regulates antiviral signalling by mediating RIG-I deubiquitination via CYLD
Syndecans are transmembrane proteoglycans implicated in diverse cellular activities. Here the authors show that Syndecan-4 via its cytosolic domain negatively regulates antiviral immunity by enhancing RIG-I interaction with a deubiquitinating enzyme CYLD, thus inhibiting the activating K63-linked RIG-I ubiquitination.
- Wei Lin
- , Jing Zhang
- & Qinmiao Sun
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Article
| Open AccessUbiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1
Mutations in LRRK2 are linked to Parkinson’s Disease. Here, the authors identify WSB1 as a LRRK2 interacting protein and find that it promotes LRRK2 aggregation in primary neurons and drosophila models via ubiquitin K27 and K29 linkages.
- Frederick C. Nucifora Jr
- , Leslie G. Nucifora
- & Christopher A. Ross
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Article
| Open AccessThe ubiquitin E3 ligase TRAF6 exacerbates pathological cardiac hypertrophy via TAK1-dependent signalling
TRAF6 is a ubiquitin E3 ligase regulating a number of biological processes. Here the authors show that ROS, generated during pathological cardiac stress, induces TRAF6 auto-ubiquitination and activation, promoting its interaction with and ubiquitination of TAK1 that contributes to development of cardiac hypertrophy.
- Yan-Xiao Ji
- , Peng Zhang
- & Hongliang Li
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Article
| Open AccessTRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis
A cellular protease, SPP, participates in production of the mature core protein of hepatitis C virus (HCV). Here, the authors show in mouse models that SPP inhibition reduces viral propagation and pathogenesis via proteasomal degradation of the immature core protein mediated by the E3 ubiquitin ligase TRC8.
- Sayaka Aizawa
- , Toru Okamoto
- & Yoshiharu Matsuura
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Article
| Open AccessHemi-methylated DNA opens a closed conformation of UHRF1 to facilitate its histone recognition
UHRF1 is involved in the maintenance of DNA methylation, but the regulatory mechanism of this epigenetic regulator is unclear. Here, the authors show that it has a closed conformation and are able to make conclusions about the mechanism of recognition of epigenetic marks.
- Jian Fang
- , Jingdong Cheng
- & Yanhui Xu
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Article
| Open AccessELL targets c-Myc for proteasomal degradation and suppresses tumour growth
The expression of the oncogene Myc is carefully controlled and dysregulation often leads to cancer. Here, the authors describe an E3 ligase for Myc—ELL—and show that it likely controls the ubiquitination and degradation of Myc.
- Yu Chen
- , Chi Zhou
- & Wuhan Xiao
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Article
| Open AccessA unified mechanism for proteolysis and autocatalytic activation in the 20S proteasome
The proteasome, an essential molecular machine, is a threonine protease, but the evolution and the components of its proteolytic centre are unclear. Here, the authors use structural biology and biochemistry to investigate the role of proteasome active site residues on maturation and activity.
- Eva M. Huber
- , Wolfgang Heinemeyer
- & Michael Groll
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Article
| Open AccessOpen-gate mutants of the mammalian proteasome show enhanced ubiquitin-conjugate degradation
The proteasome plays a key role in proteostasis by mediating the degradation of ubiquitinated substrates. Here the authors show that an open-gate mutant of the proteasome is hyperactive towards a subset of substrates and can effectively delay the accumulation of toxic protein aggregates.
- Won Hoon Choi
- , Stefanie A. H. de Poot
- & Min Jae Lee
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Article
| Open AccessInterferon-inducible protein SCOTIN interferes with HCV replication through the autolysosomal degradation of NS5A
Hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is a critical factor for HCV RNA replication. Here the authors show that SCOTIN, an interferon beta-inducible host protein, functions to limit HCV replication by targeting viral protein NS5A for autophagosomal degradation.
- Nari Kim
- , Min-Jung Kim
- & Joo-Yeon Yoo
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Article
| Open AccessLoss of UBE3A from TH-expressing neurons suppresses GABA co-release and enhances VTA-NAc optical self-stimulation
Mesoaccumbal terminals within the VTA are known to co-release both GABA and dopamine, although the functional role of the former has yet to be determined. Here, the authors find that non-canonical GABA release is regulated by the E3-ubiquitin ligase, UBE3A, and enhances optogenetic self-stimulation.
- Janet Berrios
- , Alice M. Stamatakis
- & Benjamin D. Philpot
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Article
| Open AccessSCFFbxo22-KDM4A targets methylated p53 for degradation and regulates senescence
Cellular senescence—the permanent cessation of cell proliferation—is a process that can be deregulated in cancer and other aging-related diseases. Here the authors demonstrate that the SCFFbxo22-KDM4A complex plays an essential role during senescence as an E3 ligase that targets methylated p53 for degradation.
- Yoshikazu Johmura
- , Jia Sun
- & Makoto Nakanishi
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Article
| Open AccessNanocaged enzymes with enhanced catalytic activity and increased stability against protease digestion
Cells compartmentalize enzymes for enhanced efficiency of their metabolic pathways. Here, the authors describe a self-assembly approach to construct DNA nanocaged enzymes for enhancing catalytic activity and stability, and observe an inversed correlation between the protein size and the activity enhancement.
- Zhao Zhao
- , Jinglin Fu
- & Hao Yan
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Article
| Open AccessChromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression
Cdc48/p97 is a key component of the ubiquitin-proteasome system, acting as a ubiquitin-directed segregase to regulate multiple cellular functions. Here the authors identify UBXN-3/FAF1 as a crucial regulator of chromatin-associated protein degradation that recruits Cdc48/p97 to DNA replication forks.
- André Franz
- , Paul A. Pirson
- & Thorsten Hoppe
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Article
| Open AccessAutophagy regulates Notch degradation and modulates stem cell development and neurogenesis
The molecular mechanisms behind how autophagy may impact on developmental pathways and cell fate decisions are unclear. Here Wu et al.identify Notch receptors being taken up into ATG16L1-positive autophagosomes and, using a mouse mutant model, show that changes in autophagy can impact on stem cell fate.
- Xiaoting Wu
- , Angeleen Fleming
- & David C. Rubinsztein
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Article
| Open AccessMDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification
Vascular calcification (VC) increases morbidity and mortality in cardiovascular and metabolic diseases. Here, Kwon et al.show that calcification stimuli induce MDM2- mediated ubiquitination and proteasomal degradation of HDAC1, suggesting a possible therapeutic strategy for treatment of VC patients.
- Duk-Hwa Kwon
- , Gwang Hyeon Eom
- & Hyun Kook
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Article
| Open AccessSCFCyclin F-dependent degradation of CDC6 suppresses DNA re-replication
To ensure genome stability, cells need to restrict DNA replication to once per cell cycle. Here the authors show that Cyclin F interacts with and targets the licensing factor CDC6 for degradation, preventing re-firing of replication origins.
- David Walter
- , Saskia Hoffmann
- & Claus Storgaard Sørensen
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Article
| Open Accessp38γ and δ promote heart hypertrophy by targeting the mTOR-inhibitory protein DEPTOR for degradation
mTOR signalling pathway is a critical regulator of cardiac hypertrophy. Here the authors show that two kinases, p38γ and p38δ, control heart growth by promoting mTOR activity via phosphorylation and consequent proteasome degradation of mTOR inhibitor DEPTOR, extending our knowledge of cardiac hypertrophy regulation.
- Bárbara González-Terán
- , Juan Antonio López
- & Guadalupe Sabio
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Article
| Open AccessTripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system
Degrons are determinants within proteins that direct programmed degradation by the ubiquitinproteasome system. Here, the authors propose a three-part degron architecture which contains an E3-ligase recognition motif, a ubiquitination site(s), and a disordered site to initiate degradation.
- Mainak Guharoy
- , Pallab Bhowmick
- & Peter Tompa
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Article
| Open AccessCellobiohydrolase 1 from Trichoderma reesei degrades cellulose in single cellobiose steps
Cellobiohydrolases are promising tools in biofuel production by hydrolysing cellulose into cellobiose. Here the authors use optical tweezers to show that Cellobiohydrolase 1 fromTricodermia reeseifunctions processively against moderate load, and likely uses multiple energy sources to fuel each step along the cellulose fibre.
- Sonia K. Brady
- , Sarangapani Sreelatha
- & Matthew J Lang
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Article
| Open AccessGln40 deamidation blocks structural reconfiguration and activation of SCF ubiquitin ligase complex by Nedd8
Cullin-RING ubiquitin ligases (CRLs) require neddylation of their cullin scaffolds for full activity. Here the authors use a quantitative cross-linking mass spectrometry approach to characterize three different full-length human Cul1-Rbx1 complexes to shed light on how neddylation regulates the activity of CRLs.
- Clinton Yu
- , Haibin Mao
- & Lan Huang
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Article
| Open AccessDelta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease
Age is the greatest risk factor for Alzheimer’s disease, yet how ageing regulates disease pathology is unclear. Here, the authors find that asparagine endopeptidase expression increases with age and cleaves APP, contributing to ß-amyloid production and cognitive defects in a transgenic mouse model.
- Zhentao Zhang
- , Mingke Song
- & Keqiang Ye
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Article
| Open AccessTargeting of SUMO substrates to a Cdc48–Ufd1–Npl4 segregase and STUbL pathway in fission yeast
The small ubiquitin-like modifier SUMO can be conjugated to hundreds of protein species to affect their stability or activity. Here the authors use a quantitative proteomics approach to identify sumoylated proteins modified by the STUbL and Ufd1 pathways in fission yeast.
- Julie Bonne Køhler
- , Triin Tammsalu
- & Geneviève Thon
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Article
| Open AccessThe paracaspase MALT1 cleaves HOIL1 reducing linear ubiquitination by LUBAC to dampen lymphocyte NF-κB signalling
MALT1 mediates NFκB activation. Here the authors perform proteomic analysis of human immunodeficient mutant MALT1 B cells revealing that MALT1 cleaves the HOIL1 subunit of the linear ubiquitin chain assembly complex to dampen late NFκB activation and to invoke negative feedback of NFκB activation.
- Theo Klein
- , Shan-Yu Fung
- & Christopher M. Overall
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Article
| Open AccessS-nitrosylation-dependent proteasomal degradation restrains Cdk5 activity to regulate hippocampal synaptic strength
Phosphorylation of synaptic substrates by Cdk5 plays an essential role in synapse development. Here Zhang et al. reveal that S-nitrosylation of the activator of Cdk5, p35, by nitric oxide results in its degradation and reduced Cdk5 activity, leading to alterations in synaptic strength.
- Peng Zhang
- , Wing-Yu Fu
- & Nancy Y. Ip
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Article
| Open AccessDegradation of the ABA co-receptor ABI1 by PUB12/13 U-box E3 ligases
Signaling by the plant hormone abscisic acid (ABA) is regulated by the ABI1 protein phosphatase. Here Kong et al.propose that ABA signaling is fine-tuned by ubiquitination of ABI1 which promotes ABI degradation in response to ABA.
- Lingyao Kong
- , Jinkui Cheng
- & Zhizhong Gong