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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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Mengmeng Cheng, Shurong Hu, Zhengting Wang, Yaofei Pei, Rong Fan, Xiqiang Liu, Lei Wang, Jie Zhou, Sichang Zheng, Tianyu Zhang, Yun Lin, Maochen Zhang, Ran Tao, Jie Zhong
Neddylation, a newly identified post-translational modification, is significant for the activity and stability of target proteins. The exact role of neddylation in the pathogenesis of inflammatory bowel disease, specifically those mediated by dendritic cells (DCs), was still rarely reported. Here, we showed that inhibition of neddylation protected mice from mucosal inflammation. Targeting neddylation also inhibited DC maturation characterized by reduced cytokine production, down-regulated costimulatory molecules and suppressed capacity in allogeneic T cell stimulation...
May 21, 2016: Oncotarget
Xiaofang Wang, Wenjuan Zhang, Zi Yan, Yupei Liang, Lihui Li, Xiaoli Yu, Yan Feng, Shen Fu, Yanmei Zhang, Hu Zhao, Jinha Yu, Lak Shin Jeong, Xiaomao Guo, Lijun Jia
Salvage radiotherapy (SRT) is the first-line treatment for prostate cancer patients with biochemical recurrence following radical prostatectomy, and new specific radiosensitizers are in urgent need to enhance SRT effect. MLN4924 (also known as Pevonedistat), a specific inhibitor of NEDD8-activating enzyme, has recently entered phase I/II clinical trials in several malignancies. By inhibiting cullin neddylation, MLN4924 inactivates Cullin-RING ligases (CRL), which have been validated as an attractive radiosensitizing target...
May 20, 2016: Oncotarget
Yi Zhang, Cheng-Cheng Shi, Hua-Peng Zhang, Gong-Quan Li, Shan-Shan Li
Neddylation is a post-translational protein modification process associated with carcinogenesis and cancer development. MLN4924, a pharmaceutical neddylation inhibitor, induces potent anti-cancer effects in multiple types of cancers. In this study, we investigated the effects of MLN4924 on human osteosarcoma (OS). Levels of both NEDD8 activating enzyme E1 (NAE1) and ubiquitin-conjugating enzyme E2M (Ube2M), two critical components of the neddylation pathway, were much higher in OS tissues and cells than in normal osseous tissues and cells...
May 19, 2016: Oncotarget
Yongcan Chen, Wei-Guo Zhu
DNA damage response (DDR) signaling network is initiated to protect cells from various exogenous and endogenous damage resources. Timely and accurate regulation of DDR proteins is required for distinct DNA damage repair pathways. Post-translational modifications of histone and non-histone proteins play a vital role in the DDR factor foci formation and signaling pathway. Phosphorylation, ubiquitylation, SUMOylation, neddylation, poly(ADP-ribosyl)ation, acetylation, and methylation are all involved in the spatial-temporal regulation of DDR, among which phosphorylation and ubiquitylation are well studied...
July 2016: Acta Biochimica et Biophysica Sinica
Xiaochen Zhou, Mingjia Tan, Mukesh K Nyati, Yongchao Zhao, Gongxian Wang, Yi Sun
MLN4924, also known as pevonedistat, is the first-in-class inhibitor of NEDD8-activating enzyme, which blocks the entire neddylation modification of proteins. Previous preclinical studies and current clinical trials have been exclusively focused on its anticancer property. Unexpectedly, we show here, to our knowledge for the first time, that MLN4924, when applied at nanomolar concentrations, significantly stimulates in vitro tumor sphere formation and in vivo tumorigenesis and differentiation of human cancer cells and mouse embryonic stem cells...
May 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
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