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Claire Heride, Daniel J Rigden, Erithelgi Bertsoulaki, Danilo Cucchi, Enrico De Smaele, Michael J Clague, Sylvie Urbé
USP21 is a centrosome-associated deubiquitylase (DUB) that has been implicated in the formation of primary cilia, critical organelles for the regulation of the Hedgehog (Hh) signaling pathway in vertebrates. Here we identify KCTD6, a Cullin3 E3-ligase substrate adapter previously linked to Hh-signaling, as well as Gli1, the key transcription factor responsible for Hh signal amplification, as novel interacting partners of USP21. We identify a cryptic structured protein interaction domain in KCTD6, which is predicted to bear fold similarity to Smr domains...
September 12, 2016: Journal of Cell Science
Isabel Leung, Ayelet Dekel, Julia M Shifman, Sachdev S Sidhu
A detailed understanding of the molecular mechanisms whereby ubiquitin (Ub) recognizes enzymes in the Ub proteasome system is crucial for understanding the biological function of Ub. Many structures of Ub complexes have been solved and, in most cases, reveal a large structural epitope on a common face of the Ub molecule. However, owing to the generally weak nature of these interactions, it has been difficult to map in detail the functional contributions of individual Ub side chains to affinity and specificity...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
Liang Peng, Yi Hu, Demeng Chen, Shunchang Jiao, Shengkun Sun
USP family proteins play essential roles in cancer cell proliferation and apoptosis and represent as candidate targets for cancer therapeutics. However, the effects and underlying mechanism of USP21 on renal cell carcinomas (RCC) remain unclear. In the present study, we investigate the effects of USP21 on proliferation, invasion and cancer stem cells (CSCs) property of RCC cell lines. As a result, siRNA-mediated depletion of USP21 inhibits cell proliferation, invasion ability and decreases the CSCs percentage of RCC cell lines...
May 31, 2016: Oncotarget
Saikat Bhattacharya, Divya Reddy, Arvind Ingle, Bharat Khade, Sanjay Gupta
Aberrant changes in histone post-translational modifications are encountered frequently in diseases like cancer. Although histone H3 post-translational modifications have been extensively studied in context of diseases, the functionally important histone H2A PTM H2A119ub (H2Aub) has not gained much attention. In this study, we report that H2Aub markedly decreases in hepatocellular carcinoma. Usp21, a H2A deubiquitinase, is probably responsible for decrease in H2Aub. In addition, the H2Aub levels showed an inverse correlation with H3S10 phosphorylation (H3S10p) and the proliferative state of the cells...
October 2016: Experimental Biology and Medicine
Gorka Prieto, Asier Fullaondo, Jose A Rodríguez
Large-scale sequencing projects are uncovering a growing number of missense mutations in human tumors. Understanding the phenotypic consequences of these alterations represents a formidable challenge. In silico prediction of functionally relevant amino acid motifs disrupted by cancer mutations could provide insight into the potential impact of a mutation, and guide functional tests. We have previously described Wregex, a tool for the identification of potential functional motifs, such as nuclear export signals (NESs), in proteins...
2016: Scientific Reports
Abid Khan, Sumanprava Giri, Yating Wang, Arindam Chakraborty, Archit K Ghosh, Aparna Anantharaman, Vasudha Aggarwal, Kizhakke M Sathyan, Taekjip Ha, Kannanganattu V Prasanth, Supriya G Prasanth
Ribosome biogenesis dictates the translational capacity of cells. Several mechanisms establish and maintain transcriptional output from eukaryotic ribosomal DNA (rDNA) loci. rDNA silencing is one such mechanism that ensures the inactivity and hence the maintenance of a silenced state of a subset of rRNA gene copies. Whereas oncogenic agents stimulate rRNA gene transcription, tumor suppressors decrease rRNA gene transcription. We demonstrate in mammalian cells that BANP, E5R, and Nac1 (BEN) domain 3 (BEND3), a quadruple BEN domain-containing protein, localizes in nucleoli and binds to ribosomal RNA gene promoters to help repress rRNA genes...
July 7, 2015: Proceedings of the National Academy of Sciences of the United States of America
Jaspreet Pannu, Jad I Belle, Michael Förster, Claudia U Duerr, Shiyang Shen, Leanne Kane, Katherine Harcourt, Jörg H Fritz, Simon Clare, Anastasia Nijnik
USP21 is a ubiquitin specific protease that catalyzes protein deubiquitination, however the identification of its physiological substrates remains challenging. USP21 is known to deubiquitinate transcription factor GATA3 and death-domain kinase RIPK1 in vitro, however the in vivo settings where this regulation plays a biologically significant role remain unknown. In order to determine whether USP21 is an essential and non-redundant regulator of GATA3 or RIPK1 activity in vivo, we characterized Usp21-deficient mice, focusing on mouse viability and development, hematopoietic stem cell function, and lymphocyte differentiation...
2015: PloS One
Lianqin Tao, Chen Chen, Huihui Song, Miranda Piccioni, Guochao Shi, Bin Li
Interleukin-33 (IL-33) is a dual-function protein that acts both as a secreted cytokine and as a nuclear factor regulating gene transcription. It has been demonstrated that IL-33 exerts its nuclear function in promoting the transcription of NF-κB p65. Here, we show that USP21-mediated deubiquitination of IL-33 affects the transcription of p65. IL-33 can be post-translationally modified by ubiquitination. Ubiquitin-specific protease 21 (USP21) interacts with IL-33 and also localizes in nucleus. The protein stability of IL-33 is maintained by USP21 through deubiquitination...
2014: International Journal of Clinical and Experimental Pathology
Yihui Fan, Renfang Mao, Yang Yu, Shangfeng Liu, Zhongcheng Shi, Jin Cheng, Huiyuan Zhang, Lei An, Yanling Zhao, Xin Xu, Zhenghu Chen, Mari Kogiso, Dekai Zhang, Hong Zhang, Pumin Zhang, Jae U Jung, Xiaonan Li, Guotong Xu, Jianhua Yang
Lys63-linked polyubiquitination of RIG-I is essential in antiviral immune defense, yet the molecular mechanism that negatively regulates this critical step is poorly understood. Here, we report that USP21 acts as a novel negative regulator in antiviral responses through its ability to bind to and deubiquitinate RIG-I. Overexpression of USP21 inhibited RNA virus-induced RIG-I polyubiquitination and RIG-I-mediated interferon (IFN) signaling, whereas deletion of USP21 resulted in elevated RIG-I polyubiquitination, IRF3 phosphorylation, IFN-α/β production, and antiviral responses in MEFs in response to RNA virus infection...
February 10, 2014: Journal of Experimental Medicine
Markus Riester, Lillian Werner, Joaquim Bellmunt, Shamini Selvarajah, Elizabeth A Guancial, Barbara A Weir, Edward C Stack, Rachel S Park, Robert O'Brien, Fabio A B Schutz, Toni K Choueiri, Sabina Signoretti, Josep Lloreta, Luigi Marchionni, Enrique Gallardo, Federico Rojo, Denise I Garcia, Yvonne Chekaluk, David J Kwiatkowski, Bernard H Bochner, William C Hahn, Azra H Ligon, Justine A Barletta, Massimo Loda, David M Berman, Philip W Kantoff, Franziska Michor, Jonathan E Rosenberg
PURPOSE: Metastatic urothelial carcinoma of the bladder is associated with multiple somatic copy-number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy. EXPERIMENTAL DESIGN: We obtained overall survival (OS) and array DNA copy-number data from patients with metastatic urothelial carcinoma in two cohorts. Associations between recurrent SCNAs and OS were determined by a Cox proportional hazard model adjusting for performance status and visceral disease...
April 1, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hiroshi Okuda, Hideki Ohdan, Manabu Nakayama, Haruhiko Koseki, Takeya Nakagawa, Takashi Ito
USP21 is a deubiquitylase that catalyzes isopeptide bond hydrolysis between ubiquitin and histone H2A. Since ubiqutylated H2A (ubH2A) represses transcription, USP21 plays a role in transcriptional activation. On the other hand, the localization of USP21 suggests it has an additional function in the cytoplasm. Here, we identified a USP21 short variant (USP21SV) lacking a nuclear export signal (NES). Differential localization of USP21SV, more in the nucleus than the USP21 long variant (USP21LV), suggests they have redundant roles in the cell...
2013: PloS One
Jing Zhang, Chen Chen, Xiaoxia Hou, Yayi Gao, Fang Lin, Jing Yang, Zhimei Gao, Lina Pan, Lianqin Tao, Chijun Wen, Zhengju Yao, Andy Tsun, Guochao Shi, Bin Li
The expression of the transcription factor GATA3 in FOXP3(+) regulatory T (Treg) cells is crucial for their physiological function in limiting inflammatory responses. Although other studies have shown how T cell receptor (TcR) signals induce the up-regulation of GATA3 expression in Treg cells, the underlying mechanism that maintains GATA3 expression in Treg cells remains unclear. Here, we show how USP21 interacts with and stabilizes GATA3 by mediating its deubiquitination. In a T cell line model, we found that TcR stimulation promoted USP21 expression, which was further up-regulated in the presence of FOXP3...
March 29, 2013: Journal of Biological Chemistry
Sylvie Urbé, Han Liu, Sebastian D Hayes, Claire Heride, Daniel J Rigden, Michael J Clague
Ubiquitination is a reversible modification that influences a broad range of physiological processes. There are approximately 90 deubiquitinases (DUBs) encoded in the human genome, of which 79 are predicted to have catalytic activity. We tagged 66 DUBs with green fluorescent protein and systematically surveyed their subcellular distribution, identifying enzymes specific to the nucleus, plasma membrane, and secretory and endocytic pathways. USP21 is unique in showing clear association with both centrosomes and microtubules...
March 2012: Molecular Biology of the Cell
Iraia García-Santisteban, Sonia Bañuelos, Jose A Rodríguez
The mechanisms that regulate the nucleocytoplasmic localization of human deubiquitinases remain largely unknown. The nuclear export receptor CRM1 binds to specific amino acid motifs termed NESs (nuclear export sequences). By using in silico prediction and experimental validation of candidate sequences, we identified 32 active NESs and 78 inactive NES-like motifs in human deubiquitinases. These results allowed us to evaluate the performance of three programs widely used for NES prediction, and to add novel information to the recently redefined NES consensus...
January 1, 2012: Biochemical Journal
Yu Ye, Masato Akutsu, Francisca Reyes-Turcu, Radoslav I Enchev, Keith D Wilkinson, David Komander
Modification of proteins by ubiquitin (Ub) and Ub-like (Ubl) modifiers regulates a variety of cellular functions. The ability of Ub to form chains of eight structurally and functionally distinct types adds further complexity to the system. Ub-specific proteases (USPs) hydrolyse polyUb chains, and some have been suggested to be cross-reactive with Ubl modifiers, such as neural precursor cell expressed, developmentally downregulated 8 (NEDD8) and interferon-stimulated gene 15 (ISG15). Here, we report that USP21 cleaves Ub polymers, and with reduced activity also targets ISG15, but is inactive against NEDD8...
April 2011: EMBO Reports
P Ungaro, R Teperino, P Mirra, M Longo, M Ciccarelli, G A Raciti, C Nigro, C Miele, P Formisano, F Beguinot
AIMS/HYPOTHESIS: Overexpression of PED (also known as PEA15) determines insulin resistance and impaired insulin secretion and may contribute to progression toward type 2 diabetes. Recently, we found that the transcription factor hepatocyte nuclear factor (HNF)-4alpha binds to PED promoter and represses its transcription. However, the molecular details responsible for regulation of PED gene remain unclear. METHODS: Here we used gain and loss of function approaches to investigate the hypothesis that HNF-4alpha controls chromatin remodelling at the PED promoter in human cell lines...
July 2010: Diabetologia
Gufeng Xu, Xiaojie Tan, Hongmei Wang, Wenjing Sun, Yi Shi, Susan Burlingame, Xue Gu, Guangwen Cao, Ting Zhang, Jun Qin, Jianhua Yang
Ubiquitination and deubiquitination of receptor-interacting protein 1 (RIP1) play an important role in the positive and negative regulation of the tumor necrosis factor alpha (TNFalpha)-induced nuclear factor kappaB (NF-kappaB) activation. Using a combination of functional genomic and proteomic approaches, we have identified ubiquitin-specific peptidase 21 (USP21) as a deubiquitinase for RIP1. USP21 is constitutively associated with RIP1 and deubiquitinates RIP1 in vitro and in vivo. Notably, knockdown of USP21 in HeLa cells enhances TNFalpha-induced RIP1 ubiquitination, IkappaB kinase beta (IKKbeta), and NF-kappaB phosphorylation, inhibitor of NF-kappaB alpha (IkappaB alpha) phosphorylation and ubiquitination, as well as NF-kappaB-dependent gene expression...
January 8, 2010: Journal of Biological Chemistry
Takeya Nakagawa, Takuya Kajitani, Shinji Togo, Norio Masuko, Hideki Ohdan, Yoshitaka Hishikawa, Takehiko Koji, Toshifumi Matsuyama, Tsuyoshi Ikura, Masami Muramatsu, Takashi Ito
Transcriptional initiation is a key step in the control of mRNA synthesis and is intimately related to chromatin structure and histone modification. Here, we show that the ubiquitylation of H2A (ubH2A) correlates with silent chromatin and regulates transcriptional initiation. The levels of ubH2A vary during hepatocyte regeneration, and based on microarray expression data from regenerating liver, we identified USP21, a ubiquitin-specific protease that catalyzes the hydrolysis of ubH2A. When chromatin is assembled in vitro, ubH2A, but not H2A, specifically represses the di- and trimethylation of H3K4...
January 1, 2008: Genes & Development
L Gong, T Kamitani, S Millas, E T Yeh
Covalent conjugation of proteins by ubiquitin or ubiquitin-like molecules is an important form of post-translational modification and plays a critical role in many cellular processes. Similar to the concept of phosphorylation and dephosphorylation, these conjugates are regulated by a large number of deconjugating enzymes. Here, we report the cloning of a 2,141-base pair DNA fragment from human placenta cDNA library by a strategy that involves expressed sequence tag data base searching, polymerase chain reaction, and rapid amplification of cDNA ends...
May 12, 2000: Journal of Biological Chemistry
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