Featured
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| 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
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Article
| Open AccessA non-proteolytic role for ubiquitin in deadenylation of MHC-I mRNA by the RNA-binding E3-ligase MEX-3C
mRNA deadenylation, the first step in regulated degradation, is mediated by the action of the CCR4-NOT and PAN2-PAN3 complexes. Here the authors show that the RNA-binding E3 ubiquitin-ligase MEX-3C associates with the CCR4-NOT complex and ubiquitinates the catalytic subunit CNOT7 to regulate its deadenylation activity.
- Florencia Cano
- , Radu Rapiteanu
- & Paul J. Lehner
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Article
| Open AccessATP binding to neighbouring subunits and intersubunit allosteric coupling underlie proteasomal ATPase function
The 26S proteasome contains a hexamer of ATPase subunits, which binds, unfolds and translocates substrates in an ATP-dependent manner. Kim et al. use FRET to show that ATP binding preferentially occurs at neighbouring subunits of the hexamer, and identify two allosteric systems that coordinate translocation.
- Young-Chan Kim
- , Aaron Snoberger
- & David M. Smith
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Article
| Open AccessInvolvement of a eukaryotic-like ubiquitin-related modifier in the proteasome pathway of the archaeon Sulfolobus acidocaldarius
Small archaeal ubiquitin-like modifiers (SAMPs) have been hypothesized to be part of an ancestral version of the ubiquitin-proteasome system. Here, Anjum et al. identify a SAMP homologous to the eukaryotic ubiquitin-related modifier-1 and show that it is processed by the 20S core proteasome in S. acidocaldarius.
- Rana S. Anjum
- , Sian M. Bray
- & Nicholas P. Robinson
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Article
| Open AccessIdentification of a novel actin-dependent signal transducing module allows for the targeted degradation of GLI1
The regulation of the Hedgehog (Hh) pathway by the kinase DYRK1A is controversial. Here the authors uncover a novel inhibitory activity of DYRK1A that functions to destabilize the Hh downstream transcription factor GLI1 by destabilizing actin and preventing the nuclear accumulation of protective MKL1/JMJD1A complexes.
- Philipp Schneider
- , Juan Miguel Bayo-Fina
- & Matthias Lauth
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Article
| Open AccessCRL4–DCAF1 ubiquitin E3 ligase directs protein phosphatase 2A degradation to control oocyte meiotic maturation
The E3 ubiquitin ligase CRL4 regulates oocyte survival through hydroxymethylation of genomic DNA. Here Yuet al. show that CRL4 is also required for oocytes to complete meiosis I by mediating the poly-ubiquitination and proteasomal degradation of the cell cycle regulator protein phosphatase 2A-A subunit.
- Chao Yu
- , Shu-Yan Ji
- & Heng-Yu Fan
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Article
| Open AccessThe SnRK2-APC/CTE regulatory module mediates the antagonistic action of gibberellic acid and abscisic acid pathways
The hormones abscisic acid and gibberellins act antagonistically in plant development and stress responses. Here Lin et al. show that the rice Tiller Enhancer protein is required for gibberellin-induced degradation of abscisic acid signalling components, uncovering mechanistic insights into hormone signalling crosstalk.
- Qibing Lin
- , Fuqing Wu
- & Jianmin Wan
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Article
| Open AccessThe mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling
RNA viral infections trigger an immune response mediated by the formation of aggregates of the MAVS protein. Here the authors show that the mitochondrial protein MARCH5 modulates this response by transferring ubiquitin to MAVS aggregates, thus promoting their proteasomal degradation.
- Young-Suk Yoo
- , Yong-Yea Park
- & Hyeseong Cho
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Article |
BMI1–RING1B is an autoinhibited RING E3 ubiquitin ligase
Polycomb repressive complex 1 (PRC1) ubiquitinates histone H2A at lysine 119. Here the authors show that the intrinsically low activity of PCGF4–RING1B, a canonical PRC1 E3 ligase, is offset by a favourable interaction with nucleosome substrates, resulting in efficient site-specific monoubiquitination.
- Asad M. Taherbhoy
- , Oscar W. Huang
- & Andrea G. Cochran
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Article
| Open AccessSUMO and ubiquitin-dependent XPC exchange drives nucleotide excision repair
The SUMO-targeted ubiquitin ligase RNF111 promotes K63-linked ubiquitylation of SUMOylated XPC after DNA damage. Here the authors show that RNF111 is responsible for sequential XPC ubiquitylation, and RNF111-mediated ubiquitylation promotes the release of XPC from damaged DNA after NER initiation.
- Loes van Cuijk
- , Gijsbert J. van Belle
- & Jurgen A. Marteijn
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Article
| Open AccessCryo-EM reveals the conformation of a substrate analogue in the human 20S proteasome core
The proteasome is a highly regulated complex fundamental for cell homeostasis and a target for cancer therapy. Here the authors use cryo-EM and single-particle analysis to obtain a detailed map of the interactions between each active sites of the core 20S proteasome and the irreversible inhibitor AdaAhx3L3VS.
- Paula C.A. da Fonseca
- & Edward P. Morris
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Article
| Open AccessThymoproteasomes produce unique peptide motifs for positive selection of CD8+ T cells
Proteasomes digest intracellular proteins into peptides that are then presented to lymphocytes as antigens. Here the authors show that a thymic epithelium-specific proteasome subunit cuts model proteins in a pattern favouring their weak binding to T cell receptor, and thus T cell positive selection.
- Katsuhiro Sasaki
- , Kensuke Takada
- & Shigeo Murata
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Article
| Open AccessCancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1–BAP1 complex
Premature truncations of ASXL1, a subunit of a deubiquitinase complex, are frequent in myeloid leukemia. Here, the authors show that expression of truncated ASXL1 in a haematopoietic precursor cell line enhances the deubiquitinase activity and leads to differentiation to the mast cell lineage.
- Anand Balasubramani
- , Antti Larjo
- & Anjana Rao
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Article
| Open AccessMitochondrial E3 ligase March5 maintains stemness of mouse ES cells via suppression of ERK signalling
The pluripotent state of mouse embryonic stem cells (mESCs) is regulated by extrinsic and intrinsic signals but the underlying mechanisms are not completely understood. Here the authors show that the E3 ligase, March5, contributes to the maintenance of the pluripotent state in mESCs via suppression of ERK activation.
- Hao Gu
- , Qidong Li
- & Mian Wu
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Degradation of Ndd1 by APC/CCdh1 generates a feed forward loop that times mitotic protein accumulation
Ndd1 activates the transcription of mitotic regulators. Here the authors show that the ubiquitin ligase complex APC/CCdh1ubiquitinates Ndd1 as well as Ndd1 target genes, creating a feedforward loop that generates an early class of substrates that accumulate at S phase and a late class that accumulate at G2.
- Julia Sajman
- , Drora Zenvirth
- & Michael Brandeis
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Article
| Open AccessUbiquitination of the Dishevelled DIX domain blocks its head-to-tail polymerization
The relaying of Wnt signals to the cytoplasm requires the formation of signalosomes through the reversible polymerization of Dishevelled (Dvl). Here the authors establish the functional consequences of ubiquitination of the Dvl DIX domain and identify deubiquitinases predicted to promote Dvl polymerization.
- Julia Madrzak
- , Marc Fiedler
- & Jason W. Chin
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REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway
REGγ, a proteasome activator, is associated with multiple oncogenic pathways in human cancers and can promote the degradation of multiple proteins including p53. Here the authors highlight a potential role for REGγ in skin cancer and propose a molecular mechanism linking p38 MAPK and Wnt signalling.
- Lei Li
- , Yongyan Dang
- & Xiaotao Li
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Article |
Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity
Phosphorylation of insulin receptor substrate (IRS)-1/2 by insulin-like growth factor (IGF)-I receptor tyrosine kinase is essential for IGF signalling. Here, the authors show that monoubiquitination of IRS-2 by the ubiquitin ligase Nedd4 recruits IRS-2 to the cell membrane and increases IRS-2 phosphorylation and IGF signalling.
- Toshiaki Fukushima
- , Hidehito Yoshihara
- & Shin-Ichiro Takahashi
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The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras signalling
Ras signalling activates the transcription factor c-Jun/AP-1, but the mechanism was unclear. Here, Chakraborty et al.describe a phosphorylation–ubiquitination cascade involving MSK1 and the E3 ubiquitin ligases Trim7 and RACO-1, which mediates c-Jun activation in Ras-driven lung tumorigenesis.
- Atanu Chakraborty
- , Markus E. Diefenbacher
- & Axel Behrens
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Article |
RECQ5-dependent SUMOylation of DNA topoisomerase I prevents transcription-associated genome instability
DNA topoisomerase I (TOP1) maintains DNA topology by relaxing supercoiled DNA during transcription. Here, the authors show that SUMOylation of TOP1 is necessary for its association with transcriptionally active RNA polymerase II and can reduce R-loops, preventing TOP1-induced DNA damage.
- Min Li
- , Subhash Pokharel
- & Yilun Liu
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Article |
The Parkinson’s-associated protein DJ-1 regulates the 20S proteasome
Mutations in the gene encoding DJ-1 are associated with early-onset familial forms of Parkinson’s disease, and several different molecular functions have been attributed to this protein. Moscovitz et al.show that DJ-1 physically binds the 20S proteasome and inhibits its degradation activity.
- Oren Moscovitz
- , Gili Ben-Nissan
- & Michal Sharon
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Article
| Open AccessCmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control
Defects in the DNA replication checkpoint can lead to genomic instability and cancer. Here the authors show that Cmr1/WDR76 participates in the DNA replication stress response and—along with several other components—defines a new cellular compartment that forms during cellular stress.
- Irene Gallina
- , Camilla Colding
- & Michael Lisby
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Article |
Suppressor of Deltex mediates Pez degradation and modulates Drosophila midgut homeostasis
The protein tyrosine phosphatase Pez controls intestinal stem cell proliferation in Drosophila by inhibiting the Hippo pathway transcription factor Yorkie. Wang et al. reveal that Pez protein stability is regulated by interactions with the E3 ubiquitin ligase Suppressor of Deltex.
- Chao Wang
- , Wenxiang Zhang
- & Lei Zhang
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Article |
Maturation of the proteasome core particle induces an affinity switch that controls regulatory particle association
Proteasome assembly requires the coordinated association of over sixty proteins and is dependent on chaperones. Wani et al.show that the core particle undergoes a maturation-associated decrease in its affinity for the chaperone Pba1-Pba2 that ensures timely association with the regulatory particle.
- Prashant S. Wani
- , Michael A. Rowland
- & Jeroen Roelofs
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Article
| Open AccessTriggering HIV polyprotein processing by light using rapid photodegradation of a tight-binding protease inhibitor
The study of HIV proteolysis during maturation and replication can be difficult since different steps in these processes occur simultaneously. Here, the authors present a photolabile HIV protease inhibitor which can be deactivated by light irradiation, allowing synchronized induction of viral maturation.
- Jiří Schimer
- , Marcela Pávová
- & Jan Konvalinka
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Article |
AAA+ chaperones and acyldepsipeptides activate the ClpP protease via conformational control
Acyldepsipeptides are natural antibiotics that function by activating the ClpP protease and deregulating proteolysis. Here, Gersch et al.show that acyldepsipeptides not only increase access to the active sites but also exert conformational control, thereby allosterically stimulating ClpP catalysis.
- Malte Gersch
- , Kirsten Famulla
- & Stephan A. Sieber
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Article |
NEDD4 controls intestinal stem cell homeostasis by regulating the Hippo signalling pathway
The Hippo pathway plays a role in regulating organ size and stem cell renewal but the regulatory mechanisms that fine-tune this pathway are not well understood. Here the authors report on the role of NEDD4 as a negative regulator of the Hippo signalling components, WW45 and LATS kinase, and in controlling cell proliferation and intestinal stem cell homeostasis.
- Sung Jun Bae
- , Myungjin Kim
- & Jae Hong Seol
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Article
| Open AccessRIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL
RIPK3 can cause necroptotic cell death via MLKL phosphorylation, and activate NLRP3 inflammasome. Here the authors show that MLKL is dispensable for NLRP3 activation by RIPK3, and highlight how different IAP proteins limit RIPK3 induced apoptosis, necroptosis and IL-1 secretion.
- Kate E. Lawlor
- , Nufail Khan
- & James E. Vince
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Article
| Open AccessUCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1α
When stabilized, HIF-1 can activate adaptation to hypoxia and metastasis. Here the authors show that upregulation of Ubiquitin C-terminal hydrolase-L1 in human cancers promotes metastasis and correlates with poor prognosis because of its role in opposing ubiquitin-mediated degradation of HIF-1.
- Yoko Goto
- , Lihua Zeng
- & Hiroshi Harada
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Proteasome assembly from 15S precursors involves major conformational changes and recycling of the Pba1–Pba2 chaperone
The barrel-shaped 20S proteasome core particle assembles via 15S intermediates through the action of Ump1 and Pba1–Pba2 chaperones. Using structural approaches, Kock et al. reveal conformational changes occurring upon formation of the nascent 20S particle leading to ejection of Pba1–Pba2.
- Malte Kock
- , Maria M. Nunes
- & Petra Wendler
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Review Article |
The role of protein clearance mechanisms in organismal ageing and age-related diseases
Proteins are subject to continuous and complex quality-control mechanisms, which ensure integrity of the proteome. Vilchez et al.review how a demise in these processes, collectively referred to as proteostasis, is linked to organismal ageing and the development of age-associated diseases.
- David Vilchez
- , Isabel Saez
- & Andrew Dillin
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Article |
Direct cellular delivery of human proteasomes to delay tau aggregation
Increasing the activity of the proteasome can prevent the accumulation of protein aggregates within the cell. Han et al.show that nanoparticle-mediated delivery of purified proteasomes to cells reduces proteotoxic stress resulting from tau overexpression, and prevents to accumulation of tau aggregates.
- Dong Hoon Han
- , Hee-Kyung Na
- & Min Jae Lee
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Article |
Large-scale analysis of lysine SUMOylation by SUMO remnant immunoaffinity profiling
Protein SUMOylation plays an important role in regulation of many cellular processes. Lamoliatte et al.use a monoclonal antibody specific for SUMO3 tryptic peptides to enhance proteomic identification of SUMOylated proteins, and dramatically expand the number of sites known to be modified by SUMO3.
- Frédéric Lamoliatte
- , Danielle Caron
- & Pierre Thibault
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Article |
αB-crystallin interacts with and prevents stress-activated proteolysis of focal adhesion kinase by calpain in cardiomyocytes
Focal adhesion kinase (FAK) is a scaffold and tyrosine kinase protein, critical for proper cardiac function under stress conditions. Here the authors show that the small heat–shock protein αB-crystallin interacts with FAK and protects it from calpain-mediated proteolysis in stressed rat cardiomyocytes.
- Michelle B. M. Pereira
- , Aline M. Santos
- & Kleber G. Franchini
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Article |
mGlu5 receptors regulate synaptic sumoylation via a transient PKC-dependent diffusional trapping of Ubc9 into spines
Sumoylation plays key roles in neurotransmission but the mechanisms regulating this post-translational system in neurons remain unclear. Here the authors show that synaptic diffusion of the sole SUMO-conjugating enzyme Ubc9 is regulated by synaptic activity via an mGlu5R-dependent signalling pathway.
- Céline Loriol
- , Frédéric Cassé
- & Stéphane Martin
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Article
| Open AccessUbiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension
Biogenesis of the primary cilium begins after cell cycle exit, but the regulatory steps for its formation are poorly defined. Here the authors show that proteasome-mediated removal of the ciliogenesis inhibitor, trichoplein, from mother centrioles initiates the first step of ciliogenesis.
- Kousuke Kasahara
- , Yoshitaka Kawakami
- & Masaki Inagaki
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Article
| Open AccessKainate receptor activation induces glycine receptor endocytosis through PKC deSUMOylation
Maintenance of proper membrane excitability is vital to neuronal function and in several neuronal types this relies on a balance between receptor-mediated excitation and inhibition. Here the authors report a crosstalk between excitatory kainate receptors and inhibitory glycine receptors that relies on the SUMOylation status of PKC.
- Hao Sun
- , Li Lu
- & Yong Li
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Article
| Open AccessRole for MMP-9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations
A role for cell adhesion molecules like nectin-3 in the mechanisms that underlie the behavioural effects of stress have been previously described. Here the authors show that the metalloproteinase matrix metalloproteinase-9 is involved in proteolysis of nectin-3 and in mediating stress induced behavioural effects in rats.
- Michael A. van der Kooij
- , Martina Fantin
- & Carmen Sandi
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Article |
Shh-mediated degradation of Hhip allows cell autonomous and non-cell autonomous Shh signalling
Hhip is a secreted inhibitor of the morphogen Sonic Hedgehog; however, cells expressing Hhip are themselves resistant to inhibition. Kwonget al. show that Hedgehog signalling in Hhip-expressing cells promotes this resistance by enhancing Hhip internalization.
- Lina Kwong
- , Maarten F. Bijlsma
- & Henk Roelink
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Article
| Open AccessScreening of DUB activity and specificity by MALDI-TOF mass spectrometry
Deubiquitylases (DUBs) remove ubiquitin chains from proteins. Here the authors develop a mass spectrometry-based DUB activity screen using unmodified diubiquitin isomers to characterize substrate specificity for 42 human DUBs, and assess the potency and selectivity of 11 DUB inhibitors.
- Maria Stella Ritorto
- , Richard Ewan
- & Matthias Trost
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Article |
High susceptibility to fatty liver disease in two-pore channel 2-deficient mice
Two-pore channel 2 has been implicated in coupling changes in cellular energy status with endolysosomal function. Grimm et al.show that mice lacking this channel display defects in endolysosomal trafficking of LDL-cholesterol and are susceptible to hepatic cholesterol overload and fatty liver disease.
- Christian Grimm
- , Lesca M. Holdt
- & Christian Wahl-Schott
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The deubiquitinating enzyme CYLD controls apical docking of basal bodies in ciliated epithelial cells
Mutations in the deubiquitinase gene CYLD are associated with cylindromatosis, a disease characterized by the development of skin appendage tumours. Eguether et al.discover that CYLD localizes to centrosomes and is required for basal body migration and docking, providing insight into its tumour suppressor activity.
- Thibaut Eguether
- , Maria A. Ermolaeva
- & Anne-Marie Tassin
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Article
| Open AccessLysosome sorting of β-glucocerebrosidase by LIMP-2 is targeted by the mannose 6-phosphate receptor
LIMP-2 is a membrane protein involved in β-glucocerebrosidase lysosomal targeting. Here Zhao et al. report structural and biochemical results showing how LIMP-2 interacts with β-glucocerebrosidase and the mannose 6-phosphate receptor, and propose a mechanism for LIMP-2-associated lysosomal targeting.
- Yuguang Zhao
- , Jingshan Ren
- & David I. Stuart
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Article
| Open AccessStructural insight into SUMO chain recognition and manipulation by the ubiquitin ligase RNF4
SUMO forms flexible polymeric chains that can interact with ubiquitin ligases, such as RNF4. Here Xu et al. have used NMR spectroscopy and biochemical experiments to investigate the interaction between SUMO and RNF4, and propose a mechanism for delivery of substrates to the ubiquitination machinery.
- Yingqi Xu
- , Anna Plechanovová
- & Steve J. Matthews
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Article |
SUMO1 modification stabilizes CDK6 protein and drives the cell cycle and glioblastoma progression
The correct timing of cyclin-dependent kinase (CDK) activity is crucial for the fidelity of the cell cycle. In this study, Bellail et al.show that CDK6 protein levels are positively regulated by SUMOylation and that this modification blocks ubiquitination and subsequent degradation.
- Anita C. Bellail
- , Jeffrey J. Olson
- & Chunhai Hao
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Article |
Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication
Protein modification by small ubiquitin-related modifier (SUMO) proteins is associated with antiviral responses. Here, the authors show that interferons increase the level of expression of SUMO proteins via a let-7 microRNA-controlled mechanism, and this contributes to the antiviral effects of interferons.
- Umut Sahin
- , Omar Ferhi
- & Valérie Lallemand-Breitenbach