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| Open AccessSelective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt DNA damage repair
Finding a selective modulator of Lys63-linked ubiquitin chains has proven very challenging. Here, the authors develop potent macrocyclic peptide binders of Lys63-linked di-ubiquitin chains that interrupt DNA damage repair and lead to apoptotic cell death.
- Ganga B. Vamisetti
- , Abhishek Saha
- & Ashraf Brik
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Article
| Open AccessInhibition of UBA6 by inosine augments tumour immunogenicity and responses
The metabolic environment of tumours has wide-ranging effects on the anti-tumour immune response and the outcome of immune therapy. Authors show here that the purine metabolite inosine enhances tumour immunogenicity and thus immune checkpoint blockade therapy response by inhibiting the ubiquitin-activating enzyme UBA6 in tumour cells.
- Lei Zhang
- , Li Jiang
- & Baokun He
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Article
| Open AccessIsoform-specific and ubiquitination dependent recruitment of Tet1 to replicating heterochromatin modulates methylcytosine oxidation
A short isoform of the Tet1 enzyme (Tet1s) that oxidizes the DNA 5-methylcytosine (5mC) mark is overexpressed in tumors. Here the authors show Tet1s, but not full length Tet1, changes localization over the cell cycle upon ubiquitination and Uhrf1 interaction and is targeted to heterochromatin during S-phase. This leads to 5mC oxidation and loss of DNA methylation in heterochromatin.
- María Arroyo
- , Florian D. Hastert
- & M. Cristina Cardoso
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| Open AccessCrystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6
Uba6 is an E1 enzyme that regulates numerous cellular processes by activating ubiquitin and FAT10 pathways. Here, the authors present crystal structures that illuminate Uba6 catalytic mechanisms and reveal inositol hexakisphosphate as a cofactor that modulates Uba6 activity.
- Lingmin Yuan
- , Fei Gao
- & Shaun K. Olsen
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Article
| Open AccessMet1-specific motifs conserved in OTUB subfamily of green plants enable rice OTUB1 to hydrolyse Met1 ubiquitin chains
Deubiquitinases (DUBs) targeting Met1-linked ubiquitin chains have important functions in mammals but are barely studied in plants. Here, the authors identify rice OTUB1 as a Met1-targeting DUB, characterize the structural determinants of this activity, and show that these features are conserved in green plants.
- Lining Lu
- , Xiaoguo Zhai
- & Feng Wang
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Article
| Open AccessNeddylation inhibition induces glutamine uptake and metabolism by targeting CRL3SPOP E3 ligase in cancer cells
Neddylation inhibition has been reported as a therapy for cancer. Here, the authors show that neddylation inhibition increases glutamine metabolism by stabilizing glutamine transporter ASCT2, therefore targeting ASCT2 improves the anti-cancer effect of neddylation inhibitors.
- Qiyin Zhou
- , Wenyu Lin
- & Yi Sun
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Article
| Open AccessDeubiquitinating enzymes and the proteasome regulate preferential sets of ubiquitin substrates
Deubiquitinases (DUBs) remove ubiquitin from its target proteins. Here, authors compare the regulatory effects of the proteasome and DUBs on the ubiquitinated proteome. They find preferential sets of substrates regulated by DUBs or by the proteasome. Moreover, they find that PARP1 is hyper-ubiquitinated in response to DUB inhibition, which increases its enzymatic activity.
- Fredrik Trulsson
- , Vyacheslav Akimov
- & Alfred C. O. Vertegaal
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Article
| Open AccessGlobal ubiquitinome profiling identifies NEDD4 as a regulator of Profilin 1 and actin remodelling in neural crest cells
Here the authors combine multi-omics approaches to uncover a role for ubiquitination and the ubiquitin ligase NEDD4 in targeting the actin binding protein Profilin 1 to regulate actin polymerisation in neural crest cells.
- Iman Lohraseb
- , Peter McCarthy
- & Quenten Schwarz
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Article
| Open AccessProteolysis of adaptor protein Mmr1 during budding is necessary for mitochondrial homeostasis in Saccharomyces cerevisiae
Mitochondria are transported to daughter cells by myosin via an adaptor protein Mmr1 during budding in yeast. Here they show that the regulated proteolysis of Mmr1 after mitochondria inheritance is required for mitochondrial homeostasis.
- Keisuke Obara
- , Taku Yoshikawa
- & Takumi Kamura
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Article
| Open AccessUbiquitin-like protein 3 (UBL3) is required for MARCH ubiquitination of major histocompatibility complex class II and CD86
Regulated trafficking of major histocompatibility complex class II and CD86 is a prerequisite of antigen presenting cell functionality. Authors show here that ubiquitin-like protein 3 is critically involved in the ubiquitination process that controls trafficking, with wide-ranging immunological consequences.
- Haiyin Liu
- , Kayla R. Wilson
- & Justine D. Mintern
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Article
| Open AccessUSP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy
The regulatory mechanisms of PD-L1 posttranslational modifications are not completely understood. Here the authors show that USP8 negatively regulates PD-L1 protein abundance by removing the K63-linked ubiquitination of PD-L1; while USP8 inhibition increases MHC-I expression and triggers anti-tumour immune responses through activating NF-κB signalling.
- Wenjun Xiong
- , Xueliang Gao
- & Jinfang Zhang
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Article
| Open AccessUbiquitin and a charged loop regulate the ubiquitin E3 ligase activity of Ark2C
Attachment of ubiquitin to proteins is tightly regulated and controls many signalling pathways. Here, the authors show that addition of ubiquitin by the RING E3 ligases Arkadia and Ark2C is enhanced by ubiquitin and a charged loop that precedes the RING domain.
- Andrej Paluda
- , Adam J. Middleton
- & Catherine L. Day
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Article
| Open AccessCotranslational N-degron masking by acetylation promotes proteome stability in plants
N-terminal protein acetylation is required for plant viability. Here the authors show that reducing N-terminal acetylation by NatA leads to an increase in global protein turnover that is facilitated by absent masking of a novel N-degron
- Eric Linster
- , Francy L. Forero Ruiz
- & Markus Wirtz
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Article
| Open AccessA structural basis for the diverse linkage specificities within the ZUFSP deubiquitinase family
ZUFSP-type enzymes cleave ubiquitin chains in a linkage-specific fashion, but members from different organisms have different specificities. Using an inter-kingdom comparison of activities and structures, the authors identify the domains responsible for this discrepancy.
- Thomas Hermanns
- , Christian Pichlo
- & Kay Hofmann
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Article
| Open AccessStructure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma
Rpn13 is a substrate receptor of the 26S proteasome and an anti-cancer drug target. Here, the authors identify and characterize XL5, a lead compound that binds to the N-terminal Pru domain of human Rpn13 (hRpn13), solve the NMR structure of XL5-ligated hRpn13 Pru and develop XL5-PROTACs that preferentially target an identified hRpn13 Pru fragment present in multiple myeloma cells.
- Xiuxiu Lu
- , Venkata R. Sabbasani
- & Kylie J. Walters
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Article
| Open AccessGenetic fusions favor tumorigenesis through degron loss in oncogenes
The impact of genetic fusions on degrons, which are motifs for ubiquitin-mediated protein degradation, has not been fully explored. Here, the authors analyse fusion genes affecting degrons in pan-cancer genomics data, validate their functional impact and find enrichment for both internal and C-terminal degron losses.
- Jing Liu
- , Collin Tokheim
- & Wenyi Wei
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Article
| Open AccessRNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination
BRCA1 dysfunction sensitizes cancer cells to PARP inhibitors (PARPi) but the underlying mechanism is unclear. Here, the authors identify RNF19A as a determinant of PARPi sensitivity, showing that RNF19A ubiquitinates BARD1, negatively regulates the BRCA1-BARD1 complex, and inhibits homologous recombination.
- Qian Zhu
- , Jinzhou Huang
- & Zhenkun Lou
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Article
| Open AccessA modular toolbox to generate complex polymeric ubiquitin architectures using orthogonal sortase enzymes
Ubiquitin (Ub) and Ub-like modifiers (Ubls) can form chains of various topologies, but preparing defined chains for functional studies remains challenging. Here, the authors develop chemoenzymatic tools to tailormake Ub/Ubl chains and study the involvement of specific Ub/SUMO chains in DNA repair.
- Maximilian Fottner
- , Maria Weyh
- & Kathrin Lang
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Article
| Open AccessCompetitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma
SOX2 is required for the maintenance of glioblastoma stem cells (GSCs). Here the authors identify that the RING family E3 ubiquitin ligase TRIM26 promotes SOX2 stability in a non-canonical ligase-independent manner and thus, increases the tumorigenicity of GSCs.
- Tatenda Mahlokozera
- , Bhuvic Patel
- & Albert H. Kim
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Article
| Open AccessArginine methylation and ubiquitylation crosstalk controls DNA end-resection and homologous recombination repair
Post-translational modifications are critical for regulating the DNA damage response. Here, the authors identify a methylation-deubiquitination crosstalk between methyltransferase PRMT1 and deubiquitinase USP11, showing that the enzymes regulate each other’s functions in DNA repair.
- Maria Pilar Sanchez-Bailon
- , Soo-Youn Choi
- & Clare C. Davies
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Article
| Open AccessThe 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag
The 20S particle is part of the 26S proteasome, but also exists as a free complex. Here, the authors outline signature activities of the 20S and combine chemical, structural, functional and proteomic assays to show that the 20S can degrade ubiquitin tags along with conjugated substrates.
- Indrajit Sahu
- , Sachitanand M. Mali
- & Michael H. Glickman
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Article
| Open AccessFBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth
Aberrant EGFR activation is commonly found in non-small cell lung cancer (NSCLC). Here the authors show that E3 ubiquitin ligase FBXL2 targets EGFR and EGFR tyrosine kinase inhibitor (TKI)-resistant mutants for proteasome-mediated degradation to inhibit EGFR-driven NSCLC growth and TKI resistance.
- Mengmeng Niu
- , Jing Xu
- & Zhi-Xiong Jim Xiao
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Article
| Open AccessPolycomb condensates can promote epigenetic marks but are not required for sustained chromatin compaction
Phase separation has been suggested as a mechanism for heterochromatin formation through condensation of heterochromatin-associated factors. Here the authors show Polycomb complex PRC1 forms condensates on chromatin. Using optogenetic tools they nucleate local Polycomb condensates to show that this phase separation leads to subsequent histone modifications and chromatin compaction.
- Jorine M. Eeftens
- , Manya Kapoor
- & Clifford P. Brangwynne
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Article
| Open AccessSPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition
Geminin-Cdt1 plays essential roles in the regulation of DNA replication. Here the authors reveal that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP prevents DNA replication over-firing and genome instability by affecting Geminin ubiquitination.
- Jian Ma
- , Qing Shi
- & Haojie Huang
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Article
| Open AccessSPOP mutation induces DNA methylation via stabilizing GLP/G9a
The molecular mechanism underlying the DNA hypermethylation phenotype observed in the SPOP-mutant prostate cancers is unclear. Here, the authors show that mutant SPOP induces global aberrant DNA methylation patterns through GLP/G9a and renders prostate cancer cells susceptible to DNA demethylating agents.
- Jianong Zhang
- , Kun Gao
- & Haojie Huang
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Article
| Open AccessHecw controls oogenesis and neuronal homeostasis by promoting the liquid state of ribonucleoprotein particles
Ribonucleoprotein (RNP) granules are responsible for mRNA transport and local translation required for neuronal and oocyte maturation. Here the authors show that loss of the Drosophila Ub ligase Hecw enlarges RNP granules, leads to a liquid to gel-like transition, and results in defective oogenesis and neuronal loss.
- Valentina Fajner
- , Fabio Giavazzi
- & Simona Polo
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Article
| Open AccessHypoxia regulates overall mRNA homeostasis by inducing Met1-linked linear ubiquitination of AGO2 in cancer cells
Met1-linked linear ubiquitination (M1-Ubi) is catalyzed by linear ubiquitin chain assembly complex (LUBAC). Here the authors show that Ago2 protein is M1-Ubi modified by LUBAC complex under hypoxia condition leading to less association of miRNA target mRNAs to Ago2 protein and de-repression of miRNA targets.
- Hailong Zhang
- , Xian Zhao
- & Jianxiu Yu
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Article
| Open AccessTime-resolved in vivo ubiquitinome profiling by DIA-MS reveals USP7 targets on a proteome-wide scale
Combining improved sample preparation, data-independent acquisition mass spectrometry and deep learning, the authors develop a workflow for more robust and precise quantitative ubiquitinome profiling. They use this method to characterize targets of the deubiquitinase USP7 and effects of USP7 inhibitors.
- Martin Steger
- , Vadim Demichev
- & Henrik Daub
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Article
| Open AccessThe ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors
Epigenetic changes are implicated in Acute myeloid leukemia (AML) tumorigenesis. Here, the authors show that the ubiquitin ligase RNF5 and its substrate RBBP4 contribute to AML development by regulating epigenetic-controlled transcription which determines AML sensitivity to HDAC inhibitors.
- Ali Khateb
- , Anagha Deshpande
- & Ze’ev A. Ronai
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Article
| Open AccessInhibition of CK1ε potentiates the therapeutic efficacy of CDK4/6 inhibitor in breast cancer
Acquisition of CDK4/6i resistance represents a major clinical challenge. Here, the authors report that inhibition of CK1ε can prevent acquisition of CDK4/6i resistance, potentiating the therapeutic efficacy of CDK4/6i in human breast cancer.
- Fabin Dang
- , Li Nie
- & Wenyi Wei
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Article
| Open AccessThe E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling
Cereblon (CRBN) is an E3 ubiquitin ligase substrate receptor that is involved in cancer cell death, although its regulation is poorly understood. Here, the authors show that Wnt ligand increases CRBN-dependent protein degradation and demonstrate CRBN’s importance in physiological Wnt signaling.
- Chen Shen
- , Anmada Nayak
- & David J. Robbins
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Article
| Open AccessAntibody toolkit reveals N-terminally ubiquitinated substrates of UBE2W
UBE2W catalyzes the ubiquitination of protein N-termini but its substrate spectrum is largely unknown. Here, the authors discover mAbs selective for peptides derived from N-terminally ubiquitinated proteins, solve the structure of a peptide-bound mAb and apply the mAbs to map endogenous UBE2W substrates by proteomics.
- Christopher W. Davies
- , Simon E. Vidal
- & James T. Koerber
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Article
| Open AccessAbraxas suppresses DNA end resection and limits break-induced replication by controlling SLX4/MUS81 chromatin loading in response to TOP1 inhibitor-induced DNA damage
Break-induced replication (BIR), a subtype of HR, is a mutagenic mechanism that leads to chromosome rearrangements. Here the authors reveal insights into the role of Abraxas in limiting excessive DNA end resection, R-loop accumulation and cells undergoing BIR-dependent mitotic DNA synthesis.
- Xiao Wu
- & Bin Wang
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Article
| Open AccessVCP maintains nuclear size by regulating the DNA damage-associated MDC1–p53–autophagy axis in Drosophila
Cells maintain a constant cytoplasm to nucleus volume ratio, although the role of DNA damage is not well explored. Here, the authors use Drosophila to connect TER94, the fly homolog of VCP, to disruption of DNA damage repair, leading to ubiquitinated Mu2 protein accumulation and enlarged nuclei.
- Ya-Chu Chang
- , Yu-Xiang Peng
- & Tzu-Kang Sang
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Article
| Open AccessProkineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury
Prokineticin-2 (Prok2) is a secreted protein involved in many physiological processes. Here, the authors show that Prok2 prevents neuronal cell ferroptosis after traumatic brain injury and its administration before cortical injury reduces neuronal degeneration, and motor and cognitive impairments.
- Zhongyuan Bao
- , Yinlong Liu
- & Jing Ji
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Article
| Open AccessNon-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance
The molecular mechanisms underlying cancer cell radioresistance need to be elucidated. In this study, the authors show that the microRNA biogenesis factor DGCR8 is stabilized by USP51 and ATM upon irradiation and by consequence it promotes the repair of DNA double-strand breaks and radioresistance by recruiting RNF168 to sites of damage.
- Qinglei Hang
- , Liyong Zeng
- & Li Ma
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Article
| Open AccessThe long non-coding RNA βFaar regulates islet β-cell function and survival during obesity in mice
Beta-cell function is often impaired in obesity through incompletely understood mechanisms. Here the authors show that the long noncoding RNA βFaar is reduced by diet-induced obesity in mice, which leads to impaired beta-cell function via miR-138-5p and survival via TRAF3 Interacting Protein 2.
- Fangfang Zhang
- , Yue Yang
- & Liang Jin
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Article
| Open AccessSite-specific ubiquitylation acts as a regulator of linker histone H1
While the role of specific posttranslational modifications (PTMs) is increasingly well understood for core histones, this is not the case for linker histone H1. Here the authors show that site-specific ubiquitylation of H1 results in distinct interactomes, regulates phase separation, and modulates assembly of chromatosomes.
- Eva Höllmüller
- , Simon Geigges
- & Florian Stengel
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Article
| Open AccessUbiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance
Necroptosis is a form of cell death characterized by membrane rupture via MLKL oligomerization, although mechanistic details remain unclear. Here, the authors show that MLKL ubiquitylation of K219 facilitates high-order membrane assembly and subsequent rupture, promoting cytotoxicity.
- Laura Ramos Garcia
- , Tencho Tenev
- & Pascal Meier
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Article
| Open AccessSam68 promotes hepatic gluconeogenesis via CRTC2
Hepatic gluconeogenesis is important for glucose homeostasis and a therapeutic target for type 2 diabetes. Here, the authors show that the RNA-binding adaptor protein Sam68 promotes the expression level of gluconeogenic genes and increases blood glucose levels by stabilizing the transcriptional coactivator CRTC2, while hepatic Sam68 deletion alleviates hyperglycemia in mice.
- Aijun Qiao
- , Junlan Zhou
- & Gangjian Qin
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Article
| Open AccessThe ubiquitylation of IL-1β limits its cleavage by caspase-1 and targets it for proteasomal degradation
Hyperactivation of inflammasome-induced IL-1β can cause immunopathology and is a feature of autoinflammatory diseases. Here, the authors show how ubiquitination of IL-1β limits its activity by targeting it for proteasomal degradation and preventing its cleavage by caspase-1.
- Swarna L. Vijayaraj
- , Rebecca Feltham
- & James E. Vince
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Article
| Open AccessIP6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion
Mediators of insulin signalling are targets of cullin-RING ubiquitin ligases (CRL) that mediate protein degradation, but the role of protein degradation in insulin signalling is incompletely understood. Here, the authors identified a glucose-responsive CRL4-COP1-ETV5 proteolytic axis that promotes insulin secretion, and is inhibited under hypoglycemia.
- Hong Lin
- , Yuan Yan
- & Feng Rao
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Article
| Open AccessCrystal structures of an E1–E2–ubiquitin thioester mimetic reveal molecular mechanisms of transthioesterification
The molecular mechanism of ubiquitin transfer from E1 to E2 enzymes is still unclear. By solving the crystal structure of a covalently trapped E1–E2–ubiquitin thioester mimetic, the authors identify two conformations of this complex which suggest an affinity switch mechanism for thioester transfer.
- Lingmin Yuan
- , Zongyang Lv
- & Shaun K. Olsen
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Article
| Open AccessProteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12
The tumor suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF) and itself a target for ubiquitylation. Here, the authors show that TRIP12 mediates branched K11-linked ubiquitylation of FBW7, to regulate its stability and thus abundance of a subset of SCFFBW7 substrates.
- Omar M. Khan
- , Jorge Almagro
- & Axel Behrens
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Article
| Open AccessVPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism
Autophagy and the ubiquitin–proteasome system (UPS) are cellular quality control processes, but their coordination remains unclear. Here, the authors show that branched ubiquitination of VPS34 functions as a switch between UPS and autophagy and has an important role in lipid metabolism in the liver.
- Yu-Hsuan Chen
- , Tzu-Yu Huang
- & Ruey-Hwa Chen
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Article
| Open AccessRING domains act as both substrate and enzyme in a catalytic arrangement to drive self-anchored ubiquitination
The mechanism by which RING E3-anchored ubiquitin chains are formed is not well understood. Here, the authors solve a crystal structure of the RING E3 enzyme TRIM21 trapped in the process of self-anchored chain elongation and provide biochemical and cellular insights into the mechanism of ubiquitin conjugation.
- Leo Kiss
- , Dean Clift
- & Leo C. James
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Article
| Open AccessMicrothermal-induced subcellular-targeted protein damage in cells on plasmonic nanosilver-modified surfaces evokes a two-phase HSP-p97/VCP response
Existing methods for inflicting cellular heat shock are limited by the time delay in achieving the desired temperature and the spatial precision that can be achieved. Here the authors report a method to induce focused thermal protein damage using plasmonic silver nanoparticles.
- Martin Mistrik
- , Zdenek Skrott
- & Jiri Bartek
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Article
| Open AccessStructural basis for the multi-activity factor Rad5 in replication stress tolerance
Rad5 is a hub connecting three replication stress tolerance pathways. Here, the authors present the 3.3 Å crystal structure of a N-terminal truncated K.lactis Rad5 construct that reveals the spatial arrangement of the HIRAN, Snf2 and RING domains and structure-guided in vitro and in vivo experiments reveal multiple activities of the yeast Rad5 HIRAN domain among them a role in binding PCNA and supporting its ubiquitination.
- Miaomiao Shen
- , Nalini Dhingra
- & Song Xiang
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Article
| Open AccesscircNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity
Circular RNAs (circRNA) is a class of non-coding RNAs that can regulate gene translation and function. Here the authors show that a circRNA, circNDUFB2, is downregulated in non-small cell lung cancer tissues, and likely contributes to anti-tumor immunity by regulating both degradation of oncoproteins and induction of innate immunity.
- Botai Li
- , Lili Zhu
- & Wenxin Qin