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Neddylation

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https://www.readbyqxmd.com/read/27864145/myd88-neddylation-negatively-regulates-myd88-dependent-nf-%C3%AE%C2%BAb-signaling-through-antagonizing-its-ubiquitination
#1
Fangxue Yan, Junhong Guan, Yanyan Peng, Xiaofeng Zheng
Myeloid differentiation factor 88 (MyD88) plays a central role in innate immunity response, however, how its activity is tightly regulated remains largely unknown. In this study, we identify MyD88 as a novel substrate of NEDD8, and demonstrate that MyD88 NEDDylation antagonizes its ubiquitination. Interestingly, in response to the stimulation of IL-1β, MyD88 NEDDylation is downregulated while its ubiquitination is upregulated. We also show that deNEDDylase NEDP1 serves as a regulator of this process. Furthermore, we demonstrate that NEDD8 negatively regulates the dimerization of MyD88 and suppresses MyD88-dependent NF-κB signaling...
November 15, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27834018/nuclear-localization-signal-sequence-is-required-for-vacm-1-cul5-dependent-regulation-of-cellular-growth
#2
Angelica N Willis, Shirley E Bradley Dean, Joe A Habbouche, Brian T Kempers, Megan L Ludwig, Aaron D Sayfie, Steven P Lewis, Stephanie Harrier, Zachary J DeBruine, Richard Garrett, Maria A Burnatowska-Hledin
VACM-1/CUL5 is a member of the cullin family of proteins involved in the E3 ligase-dependent degradation of diverse proteins that regulate cellular proliferation. The ability of VACM-1/CUL5 to inhibit cellular growth is affected by its posttranslational modifications and its localization to the nucleus. Since the mechanism of VACM-1/CUL5 translocation to the nucleus is not clear, the goal of this project was to determine the role that the putative nuclear localization signal (NLS) we identified in the VACM-1/CUL5 ((640)PKLKRQ(646)) plays in the cellular localization of VACM-1/CUL5 and its effect on cellular growth...
November 11, 2016: Cell and Tissue Research
https://www.readbyqxmd.com/read/27815049/therapeutic-effects-of-a-nedd8-activating-enzyme-inhibitor-pevonedistat-on-sclerodermatous-graft-versus-host-disease-in-mice
#3
Chien-Chun Steven Pai, Lam T Khuat, Mingyi Chen, William J Murphy, Mehrdad Abedi
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the ultimate treatment for highly malignant hematologic disease; however, the major complication-graft-versus-host disease (GVHD)-still hinders its clinical application. In addition, chronic GVHD remains the major cause of long-term morbidity and mortality after allo-HSCT. Previously we showed that bortezomib, a proteasome inhibitor, can ameliorate the sclerodermatous GVHD response while maintaining graft-versus-tumor (GVT) effects. Here we report that pevonedistat (MLN4924), an inhibitor of the Nedd8-activating enzyme, which functions upstream of the proteasome in the ubiquitin-proteasome pathway, can also show similar protective effects...
November 1, 2016: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/27783255/targeting-the-protein-ubiquitination-machinery-in-melanoma-by-the-nedd8-activating-enzyme-inhibitor-pevonedistat-mln4924
#4
Kit Man Wong, Lindsey N Micel, Heather M Selby, Aik Choon Tan, Todd M Pitts, Stacey M Bagby, Anna Spreafico, Peter J Klauck, Stephen J Blakemore, Peter F Smith, Alice McDonald, Allison Berger, John J Tentler, S Gail Eckhardt
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models...
October 25, 2016: Investigational New Drugs
https://www.readbyqxmd.com/read/27774986/targeted-inhibition-of-the-cop9-signalosome-for-treatment-of-cancer
#5
Anita Schlierf, Eva Altmann, Jean Quancard, Anne B Jefferson, René Assenberg, Martin Renatus, Matthew Jones, Ulrich Hassiepen, Michael Schaefer, Michael Kiffe, Andreas Weiss, Christian Wiesmann, Richard Sedrani, Jörg Eder, Bruno Martoglio
The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin-proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN...
October 24, 2016: Nature Communications
https://www.readbyqxmd.com/read/27682585/perturbation-of-neddylation-dependent-nf-%C3%AE%C2%BAb-responses-in-the-intestinal-epithelium-drives-apoptosis-and-inhibits-resolution-of-mucosal-inflammation
#6
Stefan F Ehrentraut, Valerie F Curtis, Ruth X Wang, Bejan J Saeedi, Heidi Ehrentraut, Joseph C Onyiah, Caleb J Kelly, Eric L Campbell, Louise E Glover, Douglas J Kominsky, Sean P Colgan
Recent work has revealed a central role for neddylation (the conjugation of a Nedd8-moiety to Cullin proteins) in the fine tuning of the NF-κB response (via Cullin-1). In the present study, we investigated the contribution of Cullin-1 neddylation and NF-κB signaling to mucosal inflammatory responses in vitro and in vivo. Initial in vitro studies using cultured intestinal epithelial cells revealed that the neddylation inhibitor MLN4924 prominently induces the deneddylation of Cullin-1. Parallel western blot, luciferase reporter and gene target assays identified MLN4924 as a potent inhibitor of intestinal epithelial NF-κB...
September 28, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27626304/direct-proximity-tagging-of-small-molecule-protein-targets-using-an-engineered-nedd8-ligase
#7
Zachary B Hill, Samuel B Pollock, Min Zhuang, James A Wells
Identifying the protein targets of bioactive small molecules remains a major problem in the discovery of new chemical probes and therapeutics. While activity-based probes and photo-cross-linkers have had success in identifying protein targets of small molecules, each technique has limitations. Here we describe a method for direct proximity tagging of proteins that bind small molecules. We engineered a promiscuous ligase based on the NEDD8 conjugating enzyme, Ubc12, which can be covalently linked to a small molecule of interest...
October 12, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27613030/immunodepletion-and-immunopurification-as-approaches-for-csn-research
#8
Amnon Golan, Ning Wei, Elah Pick
The COP9 signalosome (CSN) is an evolutionary conserved complex that is found in all eukaryotes, and implicated in regulating the activity of Cullin-RING ubiquitin Ligases (CRLs). Activity of CRLs is highly regulated; complexes are active when the cullin subunit is covalently attached to the ubiquitin like modifier, Nedd8. Neddylation/deneddylation cycles are required for proper CRLs activity, and deneddylation is performed by the CSN complex.We describe here a method utilizing resin-coupled antibodies to deplete the CSN from human cell extracts, and to obtain endogenous CSN complexes by immunopurification...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27593482/neddylation-is-required-for-herpes-simplex-virus-type-i-hsv-1-induced-early-phase-interferon-beta-production
#9
Xueying Zhang, Zhenjie Ye, Yujun Pei, Guihua Qiu, Qingyang Wang, Yunlu Xu, Beifen Shen, Jiyan Zhang
Type I interferons such as interferon-beta (IFN-β) play essential roles in the host innate immune response to herpes simplex virus type I (HSV-1) infection. The transcription of type I interferon genes is controlled by nuclear factor-κB (NF-κB) and interferon regulatory factor (IRF) family members including IRF3. NF-κB activation depends on the phosphorylation of inhibitor of κB (IκB), which triggers its ubiqitination and degradation. It has been reported that neddylation inhibition by a pharmacological agent MLN4924 potently suppresses lipopolysaccharide (LPS)-induced proinflammatory cytokine production with the accumulation of phosphorylated IκBα...
September 2016: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/27591266/neddylation-e2-ube2f-promotes-the-survival-of-lung-cancer-cells-by-activating-crl5-to-degrade-noxa-via-the-k11-linkage
#10
Weihua Zhou, Jie Xu, Haomin Li, Ming Xu, Zhijian J Chen, Wenyi Wei, Zhen-Qiang Pan, Yi Sun
PURPOSE: Recent studies have shown that the process of protein neddylation was abnormally activated in several human cancers. However, it is unknown whether and how UBE2F, a less characterized neddylation E2, regulates lung cancer cell survival, and whether and how NOXA, a pro-apoptotic protein, is ubiquitylated and degraded by which E3 and via which ubiquitin linkage. EXPERIMENTAL DESIGN: Methods of Immunohistochemistry and Immunoblotting were utilized to examine UBE2F protein expression...
September 2, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27543965/sag-rbx2-dependent-neddylation-regulates-t-cell-responses
#11
Nathan D Mathewson, Hideaki Fujiwara, Shin-Rong Wu, Tomomi Toubai, Katherine Oravecz-Wilson, Yaping Sun, Corinne Rossi, Cynthia Zajac, Yi Sun, Pavan Reddy
Neddylation is a crucial post-translational modification that depends on the E3 cullin ring ligase (CRL). The E2-adapter component of the CRL, sensitive to apoptosis gene (SAG), is critical for the function of CRL-mediated ubiquitination; thus, the deletion of SAG regulates neddylation. We examined the role of SAG-dependent neddylation in T-cell-mediated immunity using multiple approaches: a novel T-cell-specific, SAG genetic knockout (KO) and chemical inhibition with small-molecule MLN4924. The KO animals were viable and showed phenotypically normal mature T-cell development...
October 2016: American Journal of Pathology
https://www.readbyqxmd.com/read/27542266/dcun1d3-activates-scfskp2-ubiquitin-e3-ligase-activity-and-cell-cycle-progression-under-uv-damage
#12
Shuai Zhang, Jing Huang, Taiping Shi, Fanlei Hu, Li Zhang, Ping-Kun Zhou, Dalong Ma, Teng Ma, Xiaoyan Qiu
Our previous study showed that knockdown the endogenous expression of DCUN1D3 (also called SCCRO3 or DCNL3) blocked the S phase progression after UV irradiation. Here, we show that the silence of DCUN1D3 can increase the cyclin-dependent kinase inhibitor p27 protein levels after UV irradiation. Through Co-immunoprecipitation experiments, we found that DCUN1D3 bound to CAND1. And DCUN1D3 knockdown synergized with CAND1 over-expression in arresting the S phase. Given the CAND1's established role in Cullin-1 neddylation, we found Cullin-1 was less neddylated in DCUN1D3 deficient cells...
August 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27440184/post-translational-regulation-of-mirna-pathway-components-ago1-and-hyl1-in-plants
#13
REVIEW
Seok Keun Cho, Moon Young Ryu, Pratik Shah, Christian Peter Poulsen, Seong Wook Yang
Post-translational modifications (PTMs) of proteins are essential to increase the functional diversity of the proteome. By adding chemical groups to proteins, or degrading entire proteins by phosphorylation, glycosylation, ubiquitination, neddylation, acetylation, lipidation, and proteolysis, the complexity of the proteome increases, and this then influences most biological processes. Although small RNAs are crucial regulatory elements for gene expression in most eukaryotes, PTMs of small RNA microprocessor and RNA silencing components have not been extensively investigated in plants...
August 31, 2016: Molecules and Cells
https://www.readbyqxmd.com/read/27381497/neddylation-promotes-stress-granule-assembly
#14
Aravinth Kumar Jayabalan, Anthony Sanchez, Ra Young Park, Sang Pil Yoon, Gum-Yong Kang, Je-Hyun Baek, Paul Anderson, Younghoon Kee, Takbum Ohn
Stress granules (SGs) harbour translationally stalled messenger ribonucleoproteins and play important roles in regulating gene expression and cell fate. Here we show that neddylation promotes SG assembly in response to arsenite-induced oxidative stress. Inhibition or depletion of key components of the neddylation machinery concomitantly inhibits stress-induced polysome disassembly and SG assembly. Affinity purification and subsequent mass-spectrometric analysis of Nedd8-conjugated proteins from translationally stalled ribosomal fractions identified ribosomal proteins, translation factors and RNA-binding proteins (RBPs), including SRSF3, a previously known SG regulator...
2016: Nature Communications
https://www.readbyqxmd.com/read/27378813/romk-expression-remains-unaltered-in-a-mouse-model-of-familial-hyperkalemic-hypertension-caused-by-the-cul3%C3%AE-403-459-mutation
#15
Meena Murthy, Thimo Kurz, Kevin M O'Shaughnessy
Familial hyperkalemic hypertension (FHHt) is a rare inherited form of salt-dependent hypertension caused by mutations in proteins that regulate the renal Na(+)-Cl(-) cotransporter NCC Mutations in four genes have been reported to cause FHHt including CUL3 (Cullin3) that encodes a component of a RING E3 ligase. Cullin-3 binds to WNK kinase-bound KLHL3 (the substrate recognition subunit of the ubiquitin ligase complex) to promote ubiquitination and proteasomal degradation of WNK kinases. Deletion of exon 9 from CUL3 (affecting residues 403-459, CUL3(Δ403-459)) causes a severe form of FHHt (PHA2E) that is recapitulated closely in a knock-in mouse model...
July 2016: Physiological Reports
https://www.readbyqxmd.com/read/27348078/neddylation-requires-glycyl-trna-synthetase-to-protect-activated-e2
#16
Zhongying Mo, Qian Zhang, Ze Liu, Janelle Lauer, Yi Shi, Litao Sun, Patrick R Griffin, Xiang-Lei Yang
Neddylation is a post-translational modification that controls the cell cycle and proliferation by conjugating the ubiquitin-like protein NEDD8 to specific targets. Here we report that glycyl-tRNA synthetase (GlyRS), an essential enzyme in protein synthesis, also plays a critical role in neddylation. In human cells, knockdown of GlyRS, but not knockdown of a different tRNA synthetase, decreased the global level of neddylation and caused cell-cycle abnormality. This function of GlyRS is achieved through direct interactions with multiple components of the neddylation pathway, including NEDD8, E1, and E2 (Ubc12)...
August 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27307117/posttranslational-control-of-hur-function
#17
Ioannis Grammatikakis, Kotb Abdelmohsen, Myriam Gorospe
The RNA-binding protein HuR (human antigen R) associates with numerous transcripts, coding and noncoding, and controls their splicing, localization, stability, and translation. Through its regulation of target transcripts, HuR has been implicated in cellular events including proliferation, senescence, differentiation, apoptosis, and the stress and immune responses. In turn, HuR influences processes such as cancer and inflammation. HuR function is primarily regulated through posttranslational modifications that alter its subcellular localization and its ability to bind target RNAs; such modifications include phosphorylation, methylation, ubiquitination, NEDDylation, and proteolytic cleavage...
June 16, 2016: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/27285984/microrna-218-inhibits-emt-migration-and-invasion-by-targeting-sfmbt1-and-dcun1d1-in-cervical-cancer
#18
Zhaojing Jiang, Qiancheng Song, Rong Zeng, Jing Li, Jingyu Li, Xiaochun Lin, Xing Chen, Jiren Zhang, Yanfang Zheng
Repeated infection with high-risk HPV is a major cause for the development and metastasis of human cervical cancer, even though the mechanism of the metastasis is still not completely understood. Here, we reported that miR-218 (microRNA-218) was downregulated in cervical cancer tissues, especially in metastatic cancer tissues. We found that miR-218 expression was associated with clinicopathological characteristics of patients with cervical cancer. MiR-218 overexpression inhibited Epithelial-Mesenchymal Transition (EMT), migration and invasiveness of cervical cancer cells in vitro...
June 6, 2016: Oncotarget
https://www.readbyqxmd.com/read/27245101/itch-promotes-the-neddylation-of-junb-and-regulates-junb-dependent-transcription
#19
Haiwen Li, Heng Zhu, Yang Liu, Fuchu He, Ping Xie, Lingqiang Zhang
Protein neddylation is essential for the viability of most organisms and is widely involved in the regulation of immunity, DNA damage and repair, cell signaling and cell cycle. Unlike RING-type neddylation ligases, HECT-type neddylation ligase remains less defined. Here, we show that Itch is a novel HECT-type neddylation E3 ligase and we identify JunB as a substrate of Nedd8 modification by Itch. JunB neddylation attenuates its transcriptional activity. In addition, JunB neddylation mediated by Itch promotes its ubiquitination-dependent degradation...
September 2016: Cellular Signalling
https://www.readbyqxmd.com/read/27238229/skp1-implications-in-cancer-and-scf-oriented-anti-cancer-drug-discovery
#20
REVIEW
Muzammal Hussain, Yongzhi Lu, Yong-Qiang Liu, Kai Su, Jiancun Zhang, Jinsong Liu, Guang-Biao Zhou
In the last decade, the ubiquitin proteasome system (UPS), in general, and E3 ubiquitin ligases, in particular, have emerged as valid drug targets for the development of novel anti-cancer therapeutics. Cullin RING Ligases (CRLs), which can be classified into eight groups (CRL1-8) and comprise approximately 200 members, represent the largest family of E3 ubiquitin ligases which facilitate the ubiquitination-derived proteasomal degradation of a myriad of functionally and structurally diverse substrates. S phase kinase-associated protein 1 (Skp1)-Cullin1-F-Box protein (SCF) complexes are the best characterized among CRLs, which play crucial roles in numerous cellular processes and physiological dysfunctions, such as in cancer biology...
September 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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