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| 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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| Open AccessAromatic thiol-mediated cleavage of N–O bonds enables chemical ubiquitylation of folded proteins
Chemical approaches to site-specifically ubiquitylate a target protein allow investigation of the biochemical effects of this modification, but they often destabilize the protein. Here, the authors report on a synthetic conjugation strategy that leads to protein ubiquitylation in non-denaturing conditions.
- Caroline E. Weller
- , Abhinav Dhall
- & Champak Chatterjee
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Article
| Open AccessMARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels
Insulin receptor levels at the cell surface are reduced in insulin resistance, for reasons that are not fully understood. Here, the authors identify the E3 ubiquitin ligase MARCH1 as a direct regulator of basal insulin receptor surface levels and, therefore, insulin signalling.
- Arvindhan Nagarajan
- , Max C. Petersen
- & Narendra Wajapeyee
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| 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 AccessThe tumour suppressor CYLD regulates the p53 DNA damage response
CYLD is a deubiquitinase known to act as a tumour suppressor in different models of carcinogenesis. Here, the authors show that CYLD suppresses carcinogen-induced tumorigenesis by deubiquitinating p53 and promoting its stabilization and activation in response to DNA damage.
- Vanesa Fernández-Majada
- , Patrick-Simon Welz
- & Manolis Pasparakis
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| Open AccessA MUB E2 structure reveals E1 selectivity between cognate ubiquitin E2s in eukaryotes
Regulators of the important ubiquitylation cascade are not well studied. Here, the authors report the crystal structure of a prenylated membrane-anchored ubiquitin-fold protein from Arabidopsisbound to an E2 protein and conclude that it is an example of selective activation between E2 enzymes.
- Xiaolong Lu
- , Konstantin R. Malley
- & Brian P. Downes
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| 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 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 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 AccessCRL4Wdr70 regulates H2B monoubiquitination and facilitates Exo1-dependent resection
The repair of double-strand DNA breaks by homologous recombination requires resection of the DNA ends. Here the authors show that in Schizosaccharomyces pombe and human cells, Wdr70 is recruited as part of the CRL4 complex to promote ubiquitination of H2B and allow Exo1-mediated resection.
- Ming Zeng
- , Laifeng Ren
- & Cong Liu
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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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| Open AccessBAP1/ASXL1 recruitment and activation for H2A deubiquitination
The tumor suppressor BAP1 is activated by ASXL1 to deubiquitinate mono-ubiquitinated H2A at K119 in Polycomb gene repression. Here, the authors show how BAP1’s C-terminal extension auto-recruits it to nucleosomes, where the DEUBAD domain of ASXL1 increases BAP1’s affinity for ubiquitin to drive deubiquitination.
- Danny D. Sahtoe
- , Willem J. van Dijk
- & Titia K. Sixma
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Article
| Open AccessA cell cycle-dependent BRCA1–UHRF1 cascade regulates DNA double-strand break repair pathway choice
BRCA1 is a key regulator of DNA double-strand break repair, functioning to promote homologous recombination and repress non-homologous end-joining. Here the authors show that the ubiquitin ligase UHRF1 is recruited to breaks by BRCA1, where it targets RIF1 and thereby facilitates recombination.
- Haoxing Zhang
- , Hailong Liu
- & Huadong Pei
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Article
| Open AccessDCAF1 controls T-cell function via p53-dependent and -independent mechanisms
DCAF1 (VprBP), an HIV target protein, is a component of an ubiquitin ligase complex involved in developmental processes in plants and animals. Here, DCAF1 is shown to be vital for activation-induced T cell growth and proliferation, partly by being required for p53’s ubiquitination and degradation.
- Zengli Guo
- , Qing Kong
- & Yisong Y. Wan
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ASPM regulates symmetric stem cell division by tuning Cyclin E ubiquitination
Mutation of ASPM is associated with spindle orientation defects and microcephaly in humans. Capecchi and Pozner reveal that mice expressing truncated ASPM also display impaired neural stem cell maintenance as a result of a previously unknown requirement for ASPM in cell cycle progression.
- Mario R. Capecchi
- & Amir Pozner
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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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| Open AccessInterplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis
Krüppel-like factor 4 plays an important role in regulating responses to DNA damage, cell-fate decision and apoptosis. Here the authors show that aberrant regulation by methyltransferase PRMT5 results in failure to arrest the cell cycle and genome instability, pointing to a role in carcinogenesis.
- Dong Hu
- , Mert Gur
- & Yong Wan
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Article
| Open AccessUbiquitination switches EphA2 vesicular traffic from a continuous safeguard to a finite signalling mode
Receptor tyrosine kinases can be auto-activated independent of ligand. Sabet et al.show that on ligand stimulation, ephrin receptor EphA2 switches from auto-activation suppression by vesicular recycling to ligand-dependent signalling limited by directional trafficking to late endosomes/lysosomes.
- Ola Sabet
- , Rabea Stockert
- & Philippe I. H. Bastiaens
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Article
| Open AccessQuantitative analysis reveals how EGFR activation and downregulation are coupled in normal but not in cancer cells
Cells respond to increasing concentrations of EGF by altering the balance between EGFR phosphorylation and ubiquitination. Here the authors show that the establishment of an EGFR signaling threshold requires both a multiplicity of binding sites and cooperative binding of Cbl and Grb2 to the EGFR.
- Fabrizio Capuani
- , Alexia Conte
- & Andrea Ciliberto
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Article
| Open AccessPI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis
Mutations and post-translational modifications of the PI3K/AKT pathway inhibitor PTEN are a feature of many cancers, but these have not been associated with cervical cancer. Here, the authors identify a PI3K/AKT-mediated ubiquitination degradation pathway of PTEN that occurs in patients with cervical cancer.
- Min-Sik Lee
- , Man-Hyung Jeong
- & Jaewhan Song
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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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Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages
Activation of innate immune responses is subject to versatile regulation. Here the authors show that a conserved LATS family kinase Stk38 limits proinflammatory signalling downstream of TLR9 in macrophages and protects mice from lethal sepsis by MEKK2 ubiquitination and degradation.
- Mingyue Wen
- , Xianwei Ma
- & Huazhang An
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Article
| Open AccessAcetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer
Folate plays an essential role in dividing cells and is regulated by methionine adenosyltransferase (MAT), where a switch from MAT Iα to MAT IIα expression seems to promote liver cancer progression. Here the authors demonstrate that MAT IIα stability is regulated by acetylation and this regulation is important for tumour growth.
- Hong-Bin Yang
- , Ying-Ying Xu
- & Qun-Ying Lei
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dDsk2 regulates H2Bub1 and RNA polymerase II pausing at dHP1c complex target genes
dDsk2 is a conserved extraproteasomal ubiquitin receptor that targets ubiquitylated proteins for degradation. Here the authors report that dDsk2 regulates RNA polymerase II pausing by preventing H2Bub1 deubiquitylation, suggesting a nonproteolytic function of dDsk2.
- Roman Kessler
- , Johan Tisserand
- & Fernando Azorín
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| 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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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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Internalization and vacuolar targeting of the brassinosteroid hormone receptor BRI1 are regulated by ubiquitination
Ubiquitination of cargo proteins regulates endocytosis in yeast and mammalian cells, however the extent to which this applies to plants is less clear. Martins et al. show that both internalization and vacuolar targetting of the Arabidopsisbrassinosteroid receptor BRI1 are regulated by ubiquitination.
- Sara Martins
- , Esther M. N. Dohmann
- & Grégory Vert
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FBH1 influences DNA replication fork stability and homologous recombination through ubiquitylation of RAD51
The F-box DNA helicase 1 (FBH1) is implicated in suppression of homologous recombination (HR), but the precise mechanism is unclear. Here, the authors show that FBH1 can ubiquitylate RAD51, a central player in HR, and controls the subcellular localization of RAD51.
- Wai Kit Chu
- , Miranda J. Payne
- & Ian D. Hickson
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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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CRL4ACRBN E3 ubiquitin ligase restricts BK channel activity and prevents epileptogenesis
Ion channel mutations are implicated in epilepsy but post-translational modification of these channels is poorly understood. Here, Liu et al.show that mice with mutations in a specific E3 ubiquitin ligase that post-translationally modifies voltage-activated potassium channels may also contribute to epilepsy symptoms.
- Jiye Liu
- , Jia Ye
- & Yong Cang
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Article
| 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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Article
| 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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Article
| Open AccessThe nucleosome acidic patch plays a critical role in RNF168-dependent ubiquitination of histone H2A
The E3 ubiquitin ligase RNF168 ubiquitinates specific lysines on histone H2A as part of the DNA damage response. Here, the authors show that the acidic patch on the histone H2A/H2B dimer catalyses RNF168-dependent ubiquitination of histone 2A by redirecting ubiquitination activity towards the relevant target lysines.
- Francesca Mattiroli
- , Michael Uckelmann
- & Titia K. Sixma
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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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Article
| 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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Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60
Tip60 is a transcriptional coregulator that has an important role in differentiation. Here, Gao et al. demonstrate that the deubiquitination of Tip60 by USP7, a dominant deubiquitinating enzyme, is a key mechanism in early adipogenesis regulation.
- Yuan Gao
- , Arjen Koppen
- & Eric Kalkhoven
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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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Article
| 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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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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Article
| 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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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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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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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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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