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Ubiquitin-specific protease

Ying-Li Liu, Jing Yan, Jie Zheng, Qing-Bao Tian
The transcription factor NF-κB is a key regulator of cellular processes. A mechanism that contributes to timely termination of NF-κB activity is UPS-dependent degradation of p65 in the nucleus or on chromatin. The ubiquitin-specific protease that takes part in this process and its molecular mechanisms are shown in previous study, but which structural feature of USP48 was responsible for these effects is unknown. Here, we show that maybe the stability of NF-κB is controlled by proteasome-mediated degradation and ubiquitin-specific protease 48 (USP48), also known as synaptic ubiquitin-specific protease (synUSP) or USP31, can enhance NF-κB stability through proteasome-dependent regulation in the nucleus...
May 15, 2018: Gene
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
Sheng Zhou, Min Xiong, Guo Dai, Ling Yu, Zhengpei Zhang, Jie Chen, Weichun Guo
Osteosarcoma is the most frequent primary malignant bone tumor. An increasing body of evidence has suggested that microRNAs (miRNA/miRs) have emerged as critical regulators in the initiation and progression of osteosarcoma. The present study explored the biological function of miR-192-5p and ubiquitin-specific protease 1 (USP1), and investigated whether miR-192-5p could directly interact with USP1 in osteosarcoma. The results revealed that miR-192-5p was significantly downregulated in osteosarcoma tissues and cell lines, while a reverse expression profile of USP1 was observed...
May 2018: Oncology Letters
Avi Levin, Adi Minis, Gadi Lalazar, Jose Rodriguez, Hermann Steller
Protein degradation by the ubiquitin-proteasome system (UPS) is central to protein homeostasis and cell survival. The active 26S proteasome is a large protease complex consisting of a catalytic 20S subunit and 19S regulatory particles. Cancer cells are exposed to considerable protein overload due to high metabolic rates, reprogrammed energy metabolism and aneuploidy. Here we report a mechanism that facilitates the assembly of active 26S proteasomes in malignant cells. Upon tumorigenic transformation of the gut epithelium, 26S proteasome assembly was significantly enhanced, but levels of individual subunits were not changed...
May 1, 2018: Cancer Research
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
Hua-Rong Luo, Ying Liu, Xiao-Dong Wan, Jun-Liang Li, Min Wu, Qi-Min Zhang, Deng-Long Wu, Xin Zhao, Tian-Ru Wang
BACKGROUND/AIMS: SUMOylation is a dynamic process and reversed by the activity of SUMO-specific proteases (SENPs) family. SENP1, a member of this family, is highly expressed and plays oncogenic roles in diverse cancers including prostate cancer. However, the SENP1-transgenic mice exhibit aberrant transformation of the mouse prostate gland but do not develop cancer. Cellular Stress Response 1 (CSR1) is a tumor suppressor gene and frequently deleted in prostate cancers. Overexpression of CSR1 in prostate cancer cells inhibits colony formation, anchorage-independent growth and induces cell death...
April 25, 2018: Cellular Physiology and Biochemistry
Fei Yu, Ji-Bin Liu, Zhi-Jun Wu, Wen-Ting Xie, Xiao-Jun Zhong, Li-Kun Hou, Wei Wu, Hai-Min Lu, Xiao-Hui Jiang, Jun-Jian Jiang, Zi-Yang Cao, Gu-Jun Cong, Min-Xin Shi, Cheng-You Jia, Gai-Xia Lu, Ying-Chun Song, Li Chai, Zhong-Wei Lv, Chun-Yan Wu, Yu-Shui Ma, Da Fu
Increasing evidence has shown that microRNAs (miRNAs) play a significant functional role by directly regulating respective targets in cancer stem cell (CSC)-induced non-small cell lung cancer (NSCLC) progression and resistance to therapy. In this study, we found that hsa-miR-124a was downregulated during spheroid formation of the NSCLC cell lines SPC-A1 and NCI-H1650 and NSCLC tissues compared with normal lung cells and tissues. Patients with lower hsa-miR-124a expression had shorter overall survival (OS) and progression free survival (PFS)...
April 24, 2018: Cancer Letters
Pengcheng Luo, Cong Qin, Lihua Zhu, Chun Fang, Yan Zhang, Hai Zhang, Fei Pei, Song Tian, Xue-Yong Zhu, Gong Jun, Qing Mao, Chengcheng Xiao, Yang Su, Haizhou Zheng, Tao Xu, Jingxiao Lu, Jie Zhang
BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and inflammation, and the pathogenic mechanism of NAFLD is poorly understood. Ubiquitin-specific peptidase 10 (USP10), a member of the ubiquitin-specific protease (USP) family, is involved in environmental stress responses, tumor growth, inflammation and cellular metabolism. However, the role of USP10 in hepatic steatosis, insulin resistance and inflammation remains largely unexplored...
April 26, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Yamei Sun, Qunchao Bao, Baoqin Xuan, Wenjia Xu, Deng Pan, Qi Li, Zhikang Qian
Human cytomegalovirus (HCMV) protein pUL38 has been shown to prevent premature cell death by antagonizing cellular stress responses; however, the underlying mechanism remains unknown. In this study, we identified the host protein ubiquitin-specific protease 24 (USP24) as an interaction partner of pUL38. Mutagenesis analysis of pUL38 revealed that amino acids TFV at 227-230 were critical for its interaction with USP24. Mutant pUL38 TFV/AAA protein did not bind to USP24 and failed to prevent cell death induced by pUL38-deficient HCMV infection...
April 25, 2018: Journal of Virology
Juan Cai, Hong-Yan Chen, Shu-Jie Peng, Jun-Ling Meng, Yan Wang, Yu Zhou, Xiao-Ping Qian, Xiu-Yuan Sun, Xue-Wen Pang, Yu Zhang, Jun Zhang
Ubiquitination and deubiquitination are important post-translational regulatory mechanisms responsible for fine tuning the antiviral signaling. In this study, we identified a deubiquitinase, the ubiquitin-specific peptidase 7/herpes virus associated ubiquitin-specific protease (USP7/HAUSP) as an important negative modulator of virus-induced signaling. Overexpression of USP7 suppressed Sendai virus and polyinosinic-polycytidylic acid and poly(deoxyadenylic-deoxythymidylic)-induced ISRE and IFN-β activation, and enhanced virus replication...
April 24, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Ming Zhong, Qi Jiang, Ronghui Jin
Ubiquitin specific protease 4 (USP4) is a member of the USPs family, which catalyzes the cleavage of ubiquitin from a series of protein substrates, thereby modulating a number of cellular signaling pathways. In this study, we aimed to explore the expression profile of USP4 in lung adenocarcinoma (LUAD) using large patient cohorts in the Cancer Genome Atlas and the International Cancer Genome Consortium and to investigate its prognostic value and the possible mechanisms of its dysregulation. Results showed that USP4 was significantly downregulated in LUAD tissues (N = 514) compared with the normal controls (N = 59)...
April 17, 2018: IUBMB Life
M Emori, J Shimizu, Y Murahashi, E Mizushima, S Sugita, T Hasegawa, T Yamashita
Nodular fasciitis (NF) is a self-limiting fibrous neoplasm that can be mistaken for a soft tissue sarcoma. It is characterised by rapid growth, slight pain and local tenderness. Although it is frequently found in the forearm, a lesion distal to the wrist is quite rare. We present two unusual cases of NF involving the palm, supported by detecting ubiquitin specific protease 6 gene rearrangement. The first patient had non-intraneural NF presenting as peripheral neuropathy affecting the digital nerve while the second patient suffered from painless, non-tender NF in the palm, which had not regressed spontaneously during the five months prior to surgery...
April 16, 2018: Annals of the Royal College of Surgeons of England
Jian Sun, Qianwen Hu, Hong Peng, Cheng Peng, Liheng Zhou, Jinsong Lu, Chuanxin Huang
Connexin 43 (Cx43, also known as GJA1), is the most ubiquitously expressed connexin isoform in mammalian tissues. It forms intercellular gap junction (GJ) channels, enabling adjacent cells to communicate both electrically and metabolically. Cx43 is a short-lived protein which can be quickly degraded by the ubiquitin-dependent proteasomal, endolysosomal and autophagosomal pathways. Here, we report that the ubiquitin-specific peptidase 8 (USP8) interacts with and deubiquitinates Cx43. USP8 reduces both multiple monoubiquitination and polyubiquitination of Cx43 to prevent autophagy-mediated degradation...
April 6, 2018: Journal of Biological Chemistry
Omid Tavana, Hongbin Sun, Wei Gu
Inhibition of Mdm2 function is a validated approach to restore p53 activity for cancer therapy; nevertheless, inhibitors of Mdm2 such as Nutlin-3 have certain limitations, suggesting that additional targets in this pathway need to be further elucidated. Our finding that the Herpesvirus-Associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with the p53/Mdm2 protein complex, was one of the first examples that deubiquitinases (DUBs) exhibit a specific role in regulating protein stability. Here, we show that inhibitors of HAUSP and Nutlin-3 can synergistically activate p53 function and induce p53-dependent apoptosis in human cancer cells...
April 4, 2018: Cell Cycle
Kohei Kawaguchi, Akinori Endo, Toshiaki Fukushima, Yuka Madoka, Toshiaki Tanaka, Masayuki Komada
Nascent cargo proteins in the endoplasmic reticulum are transported to the Golgi by COPII carriers. Typical COPII vesicles are 60-70 nm in diameter, and much larger macromolecules, such as procollagen, are transported by atypical large COPII carriers in mammalian cells. The formation of large COPII carriers is enhanced by Cul3 ubiquitin ligase, which mono-ubiquitinates Sec31A, a COPII coat protein. However, the deubiquitinating enzyme for Sec31A was unclear. Here, we show that the deubiquitinating enzyme USP8 interacts with and deubiquitinates Sec31A...
March 28, 2018: Biochemical and Biophysical Research Communications
Cora Ballmann, Anne Thiel, Hannah E Korah, Anna-Carinna Reis, Wolfgang Saeger, Stefanie Stepanow, Karl Köhrer, Guido Reifenberger, Christiane B Knobbe-Thomsen, Ulrich J Knappe, Ute I Scholl
Gain-of-function somatic mutations in the ubiquitin specific protease 8 ( USP8 ) gene have recently been reported as a cause of pituitary adenomas in Cushing disease. Molecular diagnostic testing of tumor tissue may aid in the diagnosis of specimens obtained through therapeutic transsphenoidal surgery; however, for small tumors, availability of fresh tissue is limited, and contamination with normal tissue is frequent. We performed molecular testing of DNA isolated from single formalin-fixed and paraffin-embedded (FFPE) tissue sections of 42 pituitary adenomas from patients with Cushing disease (27 female patients and 15 male patients; mean age at surgery, 42...
March 1, 2018: Journal of the Endocrine Society
Shangda Yang, Ling Liu, Cheng Cao, Nan Song, Yuejiao Wang, Shuai Ma, Qi Zhang, Na Yu, Xiang Ding, Fuquan Yang, Shanshan Tian, Kai Zhang, Tao Sun, Jie Yang, Zhi Yao, Shaoyuan Wu, Lei Shi
Histone chaperone ASF1A has been reported to be dysregulated in multiple tumors; however, the underlying molecular mechanism that how the abundance and function of ASF1A are regulated remains unclear. Here we report that ASF1A is physically associated with USP52, which is previously identified as a pseudo-deubiquitinase. Interestingly, we demonstrate that USP52 is a bona fide ubiquitin-specific protease, and USP52 promotes ASF1A deubiquitination and stabilization. USP52-promoted ASF1A stabilization facilitates chromatin assembly and favors cell cycle progression...
March 29, 2018: Nature Communications
Peter Haahr, Nikoline Borgermann, Xiaohu Guo, Dimitris Typas, Divya Achuthankutty, Saskia Hoffmann, Robert Shearer, Titia K Sixma, Niels Mailand
Deubiquitylating enzymes (DUBs) enhance the dynamics of the versatile ubiquitin (Ub) code by reversing and regulating cellular ubiquitylation processes at multiple levels. Here we discovered that the uncharacterized human protein ZUFSP (zinc finger with UFM1-specific peptidase domain protein/C6orf113/ZUP1), which has been annotated as a potentially inactive UFM1 protease, and its fission yeast homolog Mug105 define a previously unrecognized class of evolutionarily conserved cysteine protease DUBs. Human ZUFSP selectively interacts with and cleaves long K63-linked poly-Ub chains by means of tandem Ub-binding domains, whereas it displays poor activity toward mono- or di-Ub substrates...
March 9, 2018: Molecular Cell
Xujing Wang, Qiqi Zhang, Yongkun Wang, Huiren Zhuang, Bo Chen
BACKGROUND Hepatocellular carcinoma (HCC) accounts for one of the most prevalent cancer types in the world. The ubiquitin specific protease 7 (USP7), a kind of deubiquitylating enzyme, has been reported to play multifaceted roles in different tumor types. The aim of this study was to investigate the expression and function of USP7 in HCC. MATERIAL AND METHODS Immunohistochemical staining and quantitative PCR were performed to explore the expression of USP7 in both HCC tissues and adjacent normal liver tissues...
March 25, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Yichao Zhao, Lingchen Gao, Longwei Xu, Renyang Tong, Nan Lin, Yuanyuan Su, Yang Yan, Yu Gao, Jie He, Lingcong Kong, Ancai Yuan, Ying Zhuge, Fang Wang, Jun Pu
Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, insulin resistance and inflammation, poses a high risk of cardiometabolic disorders. Ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme, is pivotally involved in regulating multiple inflammatory pathways; however, the role of USP4 in NAFLD is unknown. Here we report that USP4 expression was dramatically downregulated in the livers from NAFLD patients and different NAFLD mouse models induced by a high fat diet (HFD) or a genetic deficiency (ob/ob) as well as in palmitate-treated hepatocytes...
March 23, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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