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Guan-Zhong Qiu, Xiao-Yuan Mao, Yue Ma, Xing-Chun Gao, Zhen Wang, Ming-Zhu Jin, Wei Sun, Yong-Xiang Zou, Jing Lin, Hua-Lin Fu, Wei-Lin Jin
USP22 is a member of "death-from-cancer" signature, which plays a key role in cancer progression. Although previous evidence has shown that USP22 is overexpressed and correlated with poor prognosis in glioma. The effect and mechanism of USP22 in glioma malignancy especially cancer stemness remain elusive. Here, we find USP22 is more enriched in stem-like tumorspheres than differentiated glioma cells. USP22 knockdown inhibits cancer stemness in glioma cell lines. With a cell-penetrating TAT-tag protein, BMI1, a robust glioma stem-cell marker, is found to mediate the effect of USP22 on glioma stemness...
May 22, 2018: Cancer Science
Farjana Yeasmin Khusbu, Fang-Zhi Chen, Han-Chun Chen
Deubiquitinase (DUB)-mediated cleavage of ubiquitin chain balances ubiquitination and deubiquitination for determining protein fate. USP7 is one of the best characterized DUBs and functionally important. Numerous proteins have been identified as potential substrates and binding partners of USP7; those play crucial roles in diverse array of cellular and biological processes including tumour suppression, cell cycle, DNA repair, chromatin remodelling, and epigenetic regulation. This review aims at summarizing the current knowledge of this wide association of USP7 with many cellular processes that enlightens the possibility of abnormal USP7 activity in promoting oncogenesis and the importance of identification of specific inhibitors...
May 20, 2018: Cell Biochemistry and Function
Shuang Li, Jing Zhao, Dong Shang, Daniel J Kass, Yutong Zhao
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that is associated with aberrant activation of TGF-β, myofibroblast differentiation, and abnormal extracellular matrix (ECM) production. Proper regulation of protein stability is important for maintenance of intracellular protein homeostasis and signaling. Ubiquitin E3 ligases mediate protein ubiquitination, and deubiquitinating enzymes (DUBs) reverse the process. The role of ubiquitin E3 ligases and DUBs in the pathogenesis of IPF is relatively unexplored...
May 17, 2018: JCI Insight
Jinyoung Park, Eun Joo Song
Aurora B is an important kinase involved in dynamic cellular events in mitosis. Aurora B activity is controlled by several post-translational modifications (PTMs). Among them, E3 ubiquitin ligase-mediated ubiquitination plays crucial roles in controlling the relocation and degradation of Aurora B. Aurora B, ubiquitinated by different E3 ligases, moves to the exact site for its mitotic function during metaphase-anaphase transition and is then degraded for cell cycle progression at the end of mitosis. However, how the stability of Aurora B is maintained until its degradation has been poorly understood...
May 16, 2018: BMB Reports
Jung Hoon Lee, Seoyoung Park, Yejin Yun, Won Hoon Choi, Min-Ji Kang, Min Jae Lee
BACKGROUND/AIMS: The 26S proteasome is the key proteolytic complex for recognition and degradation of polyubiquitinated target substrates in eukaryotes. Among numerous proteasome-associated proteins, a deubiquitinating enzyme (DUB) USP14 has been identified as an endogenous inhibitor of the proteasome. Here, we explored the complex regulatory functions of USP14 that involve ubiquitin (Ub) homeostasis and substrate degradation in flies and mammals. METHODS: USP14-null primary and immortalized mouse embryonic fibroblasts (MEFs) and USP14 knocked-down Drosophila were analyzed in this study...
May 9, 2018: Cellular Physiology and Biochemistry
Marie Lork, Marja Kreike, Jens Staal, Rudi Beyaert
CYLD is a deubiquitinating enzyme that plays a crucial role in immunity and inflammation as a negative regulator of NF-κB transcription factor and JNK kinase signaling. Defects in either of these pathways contribute to the progression of numerous inflammatory and autoimmune disorders. Therefore, we set out to unravel molecular mechanisms that control CYLD activity in the context of T cell receptor (TCR) signaling. More specifically, we focused on CYLD phosphorylation at Ser418, which can be detected upon immunoblotting of cell extracts with phospho(Ser418)-CYLD specific antibodies...
2018: Frontiers in Cell and Developmental Biology
Kensuke Watanabe, Satoru Yokoyama, Naoki Kaneto, Takashi Hori, Yusuke Iwakami, Shinichiro Kato, Yoshihiro Hayakawa, Hiroaki Sakurai, Junya Fukuoka, Ikuo Saiki
Cancer metastasis is a major cause of mortality in cancer patients. The transcription factor SNAIL plays an important role in cancer metastasis and progression, and its expression is tightly regulated by the ubiquitin-proteasome system through the balance between ubiquitin ligases and deubiquitinating enzymes. While several ubiquitin ligases of SNAIL have been identified, it is not yet clear regarding deubiquitinating enzyme. In this study, we identified COP9 signalosome subunit 5 (COPS5) as a deubiquitinating enzyme of SNAIL by using siRNA library screening...
April 17, 2018: Oncotarget
Urszula L McClurg, Nay C T H Chit, Mahsa Azizyan, Joanne Edwards, Arash Nabbi, Karl T Riabowol, Sirintra Nakjang, Stuart R McCracken, Craig N Robson
The TP53-MDM2-AR-AKT signalling network plays a critical role in the development and progression of prostate cancer. However, the molecular mechanisms regulating this signalling network are not completely defined. By conducting transcriptome analysis, denaturing immunoprecipitations and immunopathology, we demonstrate that the TP53-MDM2-AR-AKT cross-talk is regulated by the deubiquitinating enzyme USP12 in prostate cancer. Our findings explain why USP12 is one of the 12 most commonly overexpressed cancer-associated genes located near an amplified super-enhancer...
May 14, 2018: Oncogene
Natalia D Magnani, Laura A Dada, Jacob I Sznajder
Cell homeostasis requires precise coordination of cellular protein function. Ubiquitination is a post-translational modification that modulates protein half-life and function, and is tightly regulated by ubiquitin E3 ligases and deubiquitinating enzymes. Lung injury can progress to acute respiratory distress syndrome, which is characterized by an inflammatory response and disruption of the alveolo-capillary barrier resulting in alveolar edema accumulation and hypoxemia. Ubiquitination plays an important role in the pathobiology of acute lung injury as it regulates the proteins modulating the alveolo-capillary barrier and the inflammatory response...
April 23, 2018: Translational Research: the Journal of Laboratory and Clinical Medicine
Yuekun Zhu, Chao Qu, Xuehui Hong, Yanyan Jia, Meihu Lin, Yunmei Luo, Fengqin Lin, Xiaolong Xie, Xiaoqi Xie, Juan Huang, Qin Wu, Xingfeng Qiu, Daxun Piao, Yanwei Xing, Tian Yu, Yuanfu Lu, Qiang Huang, Changyin Yu, Junfei Jin, Zhiyong Zhang
TRAF-binding domain (Trabid), one of deubiquitination enzymes, was recently reported to activate Wnt/ β-catenin signaling pathway. However, the role of Trabid in tumors including hepatocellular carcinoma (HCC) and the underlying mechanisms controlling its activity remain poorly understood. Here, we report that Trabid is significantly downregulated in HCC tumor samples and cell lines compared with normal controls and that its expression level is negatively correlated with HCC pathological grading, recurrence, and metastasis...
May 10, 2018: Cell Death and Differentiation
Peng Sun, Yue-Xin Lu, Daqing Cheng, Kuo Zhang, Jilin Zheng, Yupeng Liu, Xiaozhan Wang, Yu-Feng Yuan, Yi-Da Tang
Sterile inflammation is an essential factor causing hepatic ischemia/reperfusion (I/R) injury. As a critical regulator of inflammation, the role of monocyte chemoattractant protein-induced protein 1 (MCPIP1) in hepatic I/R injury remains undetermined. In this study, we discovered that MCPIP1 downregulation was associated with hepatic I/R injury in liver transplant patients and a mouse model. Hepatocyte-specific Mcpip1 gene knockout (HKO) and transgenic (HTG) mice demonstrated that MCPIP1 functions to ameliorate liver damage, reduce inflammation, prevent cell death, and promote regeneration...
May 9, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Naomi C Boisvert, Chet E Holterman, Jean-François Thibodeau, Rania Nasrallah, Eldjonai Kamto, Cesar H Comin, Luciano da F Costa, Anthony Carter, Richard L Hébert, Alexey Gutsol, Gregory O Cron, Baptiste Lacoste, Douglas A Gray, Chris R Kennedy
Neuronal ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that maintains intracellular ubiquitin pools and promotes axonal transport. Uchl1 deletion in mice leads to progressive axonal degeneration, affecting the dorsal root ganglion that harbours axons emanating to the kidney. Innervation is a crucial regulator of renal hemodynamics, though the contribution of neuronal UCHL1 to this is unclear. Immunofluorescence revealed significant neuronal UCHL1 expression in mouse kidney, including periglomerular axons...
May 8, 2018: Clinical Science (1979-)
Yu-Che Cheng, Sheau-Yann Shieh
Checkpoint kinase 1 (CHK1), a Ser/Thr protein kinase, is modified by the K63-linked ubiquitin chain in response to genotoxic stress, which promotes its nuclear localization, chromatin association, and activation. Interestingly, this bulky modification is linked to a critical residue, K132, at the kinase active site. It is unclear how this modification affects the kinase activity and how it is removed to enable the release of CHK1 from chromatin. Herein, we show that the K63-linked ubiquitin chain at CHK1's K132 residue has an inhibitory effect on the kinase activity...
May 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
Meghan Kerrisk Campbell, Morgan Sheng
Mutations or altered protein levels of SHANK3 are implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorders, and schizophrenia (Guilmatre et al., 2014). Loss of SHANK3 in mouse models results in decreased synapse density and reduction in the levels of multiple synaptic proteins (Jiang and Ehlers, 2013). The family of SHANK scaffolding molecules are among the most heavily ubiquitinated proteins at the postsynaptic density. The ubiquitin-dependent proteasome degradation of SHANK is regulated by synaptic activity and may contribute to activity-dependent synaptic remodeling (Ehlers, 2003; Shin et al...
May 7, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Emmy Van Quickelberghe, Arne Martens, Ludger J E Goeminne, Lieven Clement, Geert van Loo, Kris Gevaert
A20 is a negative regulator of NF-κB signaling, it controls inflammatory responses and ensures tissue homeostasis. A20 is thought to restrict NF-κB activation both by its ubiquitin-editing activity as well as by its non-enzymatic activities. Besides its role in NF-κB signaling, A20 also acts as a protective factor inhibiting apoptosis and necroptosis. Because of the ability of A20 to both ubiquitinate and deubiquitinate substrates, and its involvement in many cellular processes, we hypothesized that deletion of A20 might generally impact on protein levels, thereby disrupting cellular signaling...
May 7, 2018: Journal of Proteome Research
Qingxiang Liu, Yaoxing Wu, Yunfei Qin, Jiajia Hu, Weihong Xie, F Xiao-Feng Qin, Jun Cui
The innate immune response conferred by type I interferons is essential for host defense against viral infection but needs to be tightly controlled to avoid immunopathology. We performed a systematic functional screening by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) knockout and overexpression to investigate the roles of the deubiquitinating enzyme (DUB) family in regulating antiviral immunity. We demonstrated that the expression of a large fraction of DUBs underwent complex temporal alteration, suggesting a dynamic program of feedback regulation...
May 2018: Science Advances
Daniel A Garcia, Christina Baek, M Valeria Estrada, Tiffani Tysl, Eric J Bennett, Jing Yang, John T Chang
Epithelial-mesenchymal transition (EMT) is a conserved cellular plasticity program that is reactivated in carcinoma cells and drives metastasis. While EMT is well studied its regulatory mechanisms remain unclear. Therefore, to identify novel regulators of EMT, a data mining approach was taken using published microarray data and a group of deubiquitinases (DUBs) were found to be upregulated in cells that have undergone EMT. Here, it is demonstrated that one DUB, ubiquitin specific peptidase 11 (USP11), enhances TGFβ-induced EMT and self-renewal in immortalized human mammary epithelial cells...
May 3, 2018: Molecular Cancer Research: MCR
Xiangling Chen, Chengli Yu, Jing Gao, Hongwen Zhu, Binghai Cui, Tao Zhang, Yanting Zhou, Qian Liu, Han He, Ruoxuan Xiao, Ruimin Huang, Hua Xie, Daming Gao, Hu Zhou
The X-linked deubiquitinase, USP9X, is implicated in multiple cancers by targeting various substrates. Increased expression of USP9X is observed in non-small-cell lung cancer (NSCLC) and is correlated with poor prognosis. However, the molecular mechanism for USP9X regulation of tumor cell survival and tumorigenesis in NSCLC is less defined. Methods: In this study, chemical labeling, quantitative proteomic screening was applied to analyze A549 cells with or without USP9X RNA interference. Functional in vitro and in vivo experiments were performed to confirm the oncogenic effects of USP9X in NSCLC and to investigate the underlying mechanisms...
2018: Theranostics
Zhao Wang, Hong Zhang, Caiyun Liu, Junjie Xing, Xiao-Lin Chen
Ubiquitination is an essential protein modification in eukaryotic cells, which is reversible. Deubiquitinating enzymes (DUBs) catalyze deubiquitination process to reverse ubiquitination, maintain ubiquitin homeostasis or promote protein degradation by recycling ubiquitins. In order to investigate effects of deubiquitination process in plant pathogenic fungus Magnaporthe oryzae , we generated deletion mutants of MoUBP14 . Ortholog of MoUbp14 was reported to play general roles in ubiquitin-mediated protein degradation in Saccharomyces cerevisiae ...
2018: Frontiers in Microbiology
Wenjuan Li, Kaisa Cui, Edward V Prochownik, Youjun Li
Deubiquitinases (DUBs) play essential roles in normal cell proliferation and tumor growth. However, the molecular mechanisms of DUBs on hepatocellular carcinoma (HCC) remains largely unknown. In this study, based on analysis of several HCC datasets, we found that the USP21 gene, which encodes a member of the ubiquitin-specific protease family, is highly amplified and overexpressed in HCCs, with the extent of this up-regulation significantly correlating with poor clinical outcomes. Inhibition of USP21 in HCC cell lines decreased cell proliferation, anchorage-independent growth, cell cycle progression, and in vivo tumor growth...
April 30, 2018: Cell Death & Disease
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