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| Open AccessThe CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells
CD8 + T cells are central players in anti-tumour immunity. Here authors identify Cul5, a ubiquitin E3 ligase as an important inhibitor of CD8 + T cell anti-tumour cytotoxicity and persistence via involvement with both T cell receptor and cytokine-regulated central pathways.
- Xiaofeng Liao
- , Wenxue Li
- & Dianqing Wu
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Article
| Open AccessMYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting
SKP2 is an oncogenic E3-ubiquitin ligase. Here the authors show that SKP2 is epigenetically regulated by the muscle lineage transcription factor MYOD, supports tumorigenesis in the Fusion Negative (FN) subtype of rhabdomyosarcoma (RMS) and impairs differentiation promoting degradation of p57Kip2.
- Silvia Pomella
- , Matteo Cassandri
- & Rossella Rota
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Article
| Open AccessN-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity
The most common protein modification in eukaryotes is N-terminal acetylation, but its functional impact has remained enigmatic. Here, the authors find that a key role for N-terminal acetylation is shielding proteins from ubiquitin ligase-mediated degradation, mediating motility and longevity.
- Sylvia Varland
- , Rui Duarte Silva
- & Thomas Arnesen
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Article
| Open AccessTargeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex
Repair of topoisomerase 1 (TOP1) DNA protein crosslinks (DPC) limits the efficacy of the TOP1 inhibitor irinotecan in cancer therapy. Here, the authors identify pevonedistat, NEDD8 inhibitor, as synergistic with irinotecan by blocking neddylation-activated ubiquitin/proteasomal degradation of TOP1-DPC.
- Yilun Sun
- , Simone A. Baechler
- & Yves Pommier
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Article
| Open AccessHepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice
Dysregulation of the post-translational modification neddylation has been implicated in liver diseases such as fibrosis and hepatocellular carcinoma. Here the authors report that hepatic neddylation deficiency via genetic deletion of NEDD8 Activating Enzyme E1 Subunit 1 (NAE1) causes acute liver failure due to mitochondrial dysfunction and aberrant activation of NF-κB-inducing kinase in mice.
- Cheng Xu
- , Hongyi Zhou
- & Weiqin Chen
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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 AccessStructural and functional consequences of NEDD8 phosphorylation
Both ubiquitin and NEDD8 can be phosphorylated, but the biological role of NEDD8 phosphorylation remains unclear. Here, the authors identify similarities and differences of ubiquitin and NEDD8 phosphorylation, showing that phosphorylated NEDD8 has a distinct interactome and regulates HSP70 proteins.
- Katrin Stuber
- , Tobias Schneider
- & Martin Scheffner
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Article
| Open AccessSelective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity
Activation of cullin-RING ligases can be inhibited by targeting DCN1, but selective DCN1 inhibitors with in vivo activity are lacking. Here, the authors develop covalent DCN1 inhibitors that selectively and potently inhibit cullin-3 activation and downstream functions in cells and in mice.
- Haibin Zhou
- , Jianfeng Lu
- & Shaomeng Wang
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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 AccessStructural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome
The COP9 signalosome (CSN) regulates Cullin-RING Ligase 2 (CRL2) but the molecular basis for their interaction is unknown. Here the authors use structural mass spectrometry and cryo-EM approaches to assess the structures and dynamics of CSN-CRL2 complexes.
- Sarah V. Faull
- , Andy M. C. Lau
- & Argyris Politis
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Article
| Open AccessMolecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme
Ubiquitin and ubiquitin-like modifiers such as SUMO play important roles in several cellular pathways that can become deregulated in cancer. Here the authors describe the structural basis for inhibition of SUMO E1 ligase by the small molecule COH000.
- Zongyang Lv
- , Lingmin Yuan
- & Shaun K. Olsen
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Article
| Open AccessNEDDylation promotes nuclear protein aggregation and protects the Ubiquitin Proteasome System upon proteotoxic stress
Protein NEDDylation increases upon proteotoxic stress but the function of this response remains to be elucidated. Here, the authors show that NEDDylation contributes to the cellular defence against proteotoxicity by promoting nuclear protein aggregation and protecting the ubiquitin proteasome system.
- Chantal M. Maghames
- , Sofia Lobato-Gil
- & Dimitris P. Xirodimas
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Article |
The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis
E3 ligases that attach ubiquitin to proteins destined for proteasomal degradation are regulated by neddylation. In this study, Xie et al. show that the HECT ligase Smurf1, which is a ubiquitin ligase, is also neddylated, and this post-translational modification enhances its ligase activity.
- Ping Xie
- , Minghua Zhang
- & Lingqiang Zhang
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Article
| Open AccessCSN-mediated deneddylation differentially modulates Ci155 proteolysis to promote Hedgehog signalling responses
Hedgehog signalling gradients are required for proper wing formation inDrosophila, and Hedgehog is known to regulate the cubitus interruptus transcription factor. Here, the authors show that the COP9 signalosome has a critical role in translating a Hedgehog gradient into a cubitus interruptus gradient.
- June-Tai Wu
- , Wei-Hsiang Lin
- & Cheng-Ting Chien