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Robert M DeKroon, Harsha P Gunawardena, Rachel Edwards, Nancy Raab-Traub
The Epstein-Barr virus (EBV) oncoproteins latent membrane protein 1 (LMP1) and LMP2A constitutively activate multiple signaling pathways, and both have been shown to interact with cellular ubiquitin ligases and affect cellular ubiquitination. To detect the LMP1- and LMP2A-mediated effects on the global cellular proteome, epithelial cell lines expressing LMP1 or LMP2A were analyzed using label-free quantitative proteomics. To identify proteins whose ubiquitination is affected by the viral proteins, the cells were cultured in the presence and absence of deubiquitinase (DUB) and proteasome inhibitors...
June 19, 2018: MBio
Valentina Gambini, Martina Tilio, Eunice Wairimu Maina, Cristina Andreani, Caterina Bartolacci, Junbiao Wang, Manuela Iezzi, Stefano Ferraro, Anna Teresa Ramadori, Oumarou Camille Simon, Stefania Pucciarelli, Guojun Wu, Q Ping Dou, Cristina Marchini, Rossana Galassi, Augusto Amici
Basal like breast cancer (BLBC) is a very aggressive subtype of breast cancer giving few chances of survival, against which cisplatin based therapy is a compromise among the anticancer activity, the resistance development and the severe side effects. With the aim of finding new anticancer agents alternative to cisplatin, seven gold(I) azolate/phosphane compounds were evaluated in vitro by MTT tests in human MDA-MB-231, human mammary epithelial HMLE cells overexpressing FoxQ1, and murine A17 cells as models of BLBC...
June 2, 2018: European Journal of Medicinal Chemistry
Virginia Sanchez-Quiles, Nerea Osinalde, Vyacheslav Akimov, Irina Kratchmarova, Blagoy Blagoev
The present data article corresponds to the proteomic data of the involvement of Cylindromatosis protein (CYLD) in the ubiquitination signaling initiated by EGF stimulation. CYLD tumor suppressor protein has Lys63-chain deubiquitinase activity that has been proved essential for the negative regulation of crucial signaling mechanisms, namely the NFkB pathway. Previous results have suggested the involvement of CYLD in the EGF-dependent signal transduction as well, showing its engagement within the tyrosine-phosphorylated complexes formed following the addition of the growth factor...
June 2018: Data in Brief
Lianlian Li, Yong Wang, Xiaoyu Zhang, Guanhua Song, Qiang Guo, Zhiyong Zhang, Yutao Diao, Haipeng Yin, Hongyan Liu, Guosheng Jiang
All-trans retinoic acid (ATRA) has been used for the treatment of acute promyelocytic leukemia (APL). However, its molecular mechanisms of action are unclear. Ubiquitin-specific protease 48 (USP48) is a deubiquitinase enzyme that can post-translationally remove ubiquitin molecules from substrates. In the present study, the role of USP48 in ATRA-induced differentiation of APL cells was studied. The expression of USP48 decreased following ATRA treatment. Functionally, overexpression of USP48 using electroporation-mediated delivery inhibited the proliferation of APL cells and promoted ATRA-mediated differentiation...
June 13, 2018: International Journal of Oncology
Sarah Nicklas, Anna-Lena Hillje, Satoshi Okawa, Ina-Maria Rudolph, Franziska Melanie Collmann, Thea van Wuellen, Antonio Del Sol, Jens C Schwamborn
The balance between stem cell maintenance and differentiation has been proposed to depend on antagonizing ubiquitination and deubiquitination reactions of key stem cell transcription factors (SCTFs) mediated by pairs of E3 ubiquitin ligases and deubiquitinating enzymes. Accordingly, increased ubiquitination results in proteasomal degradation of the SCTF, thereby inducing cellular differentiation, whereas increased deubiquitination stabilizes the SCTF, leading to maintenance of the stem cell fate. In neural stem cells, one of the key SCTFs is c-Myc...
June 13, 2018: Cell Death and Differentiation
Fan Yao, Zhicheng Zhou, Jongchan Kim, Qinglei Hang, Zhenna Xiao, Baochau N Ton, Liang Chang, Na Liu, Liyong Zeng, Wenqi Wang, Yumeng Wang, Peijing Zhang, Xiaoyu Hu, Xiaohua Su, Han Liang, Yutong Sun, Li Ma
Dysregulation of YAP localization and activity is associated with pathological conditions such as cancer. Although activation of the Hippo phosphorylation cascade is known to cause cytoplasmic retention and inactivation of YAP, emerging evidence suggests that YAP can be regulated in a Hippo-independent manner. Here, we report that YAP is subject to non-proteolytic, K63-linked polyubiquitination by the SCFSKP2 E3 ligase complex (SKP2), which is reversed by the deubiquitinase OTUD1. The non-proteolytic ubiquitination of YAP enhances its interaction with its nuclear binding partner TEAD, thereby inducing YAP's nuclear localization, transcriptional activity, and growth-promoting function...
June 11, 2018: Nature Communications
Mohammed A Mansour
Dynamic modulation and posttranslational modification of proteins are tightly controlled biological processes that occur in response to physiological cues. One such dynamic modulation is ubiquitination, which marks proteins for degradation via the proteasome, altering their localization, affecting their activity, and promoting or interfering with protein interactions. Hence, ubiquitination is crucial for a plethora of physiological processes, including cell survival, differentiation and innate and adaptive immunity...
June 1, 2018: International Journal of Biochemistry & Cell Biology
Reinaldo Franqui-Machin, Mu Hao, Hua Bai, Zhimin Gu, Xin Zhan, Hasem Habelhah, Yogesh Jethava, Lugui Qiu, Ivana Frech, Guido Tricot, Fenghuang Zhan
Drug resistance remains the key problem in cancer treatment. It is now accepted that each myeloma patient harbors multiple subclones and subclone dominance may change over time. The coexistence of multiple subclones with high or low chromosomal instability (CIN) signature causes heterogeneity and drug resistance with consequent disease relapse. In this study, using a tandem affinity purification-mass spectrometry (TAP-MS) technique, we found that NEK2, a CIN gene, was bound to the deubiquitinase USP7. Binding to USP7 prevented NEK2 ubiquitination resulting in NEK2 stabilization...
June 4, 2018: Journal of Clinical Investigation
Sebastian Dorn, Christian Schoergenhofer, Michael Krainer, Markus Müller, Bernd Jilma
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known to activate the canonical NF-κB pathway similar to TNF. The exact mechanism of the entire signaling cascade is still under investigation. The involvement of linear ubiquitylation as upregulating component has already been shown recently in some cell lines, but not in human embryonic kidney 293 (HEK293) cells. The downregulating function of the ABIN-1 (A20 binding and inhibitor of NF-κB) as linear ubiquitylation antagonist has been shown in combination with some NF-κB-inducing pathways, but not with TRAIL...
2018: BioResearch Open Access
Ishita Gupta, Suruchi Aggarwal, Kanika Singh, Amit Yadav, Sameena Khan
Trypanosomiasis infects more than 21 million people and claims approximately 2 million lives annually. Due to the development of resistance against currently available anti-trypanosomal drugs, there is a growing need for specific inhibitors and novel drug targets. Of late, the proteins from the Ubiquitin Proteasome Pathway (UPP): ubiquitin ligases and deubiquitinase have received attention as potential drug targets in other parasites from the apicomplexan family. The completion of Trypanosoma cruzi (Tc) genome sequencing in 2005 and subsequent availability of database resources like TriTrypDB has provided a platform for the systematic study of the proteome of this parasite...
May 30, 2018: Scientific Reports
Annemarie Steiner, Cassandra R Harapas, Seth L Masters, Sophia Davidson
PURPOSE OF REVIEW: The nuclear factor κB (NF-κB) pathway is tightly regulated through multiple posttranslational mechanisms including ubiquitination. Mutations in these regulatory pathways can cause disease and are the focus of this review. RECENT FINDINGS: The linear ubiquitin chain assembly complex (LUBAC) is a trimer made up of HOIL-1L, SHARPIN, and the catalytic subunit HOIP. Loss of function mutations in HOIL-1L and HOIP result in largely overlapping phenotypes, characterized by multi-organ autoinflammation, immunodeficiency, and amylopectinosis...
May 30, 2018: Current Rheumatology Reports
Tom Cornelissen, Sven Vilain, Katlijn Vints, Natalia Gounko, Patrik Verstreken, Wim Vandenberghe
Mutations in the genes for PINK1 and parkin cause Parkinson's disease. PINK1 and parkin cooperate in the selective autophagic degradation of damaged mitochondria (mitophagy) in cultured cells. However, evidence for their role in mitophagy in vivo is still scarce. Here, we generated a Drosophila model expressing the mitophagy probe mt-Keima. Using live mt-Keima imaging and correlative light and electron microscopy (CLEM) we show that mitophagy occurs in muscle cells and dopaminergic neurons in vivo, even in the absence of exogenous mitochondrial toxins...
May 29, 2018: ELife
Amanda Tomie Ouchida, Merve Kacal, Adi Zheng, Gorbatchev Ambroise, Boxi Zhang, Erik Norberg, Helin Vakifahmetoglu-Norberg
Epithelial-to-mesenchymal transition (EMT) is a fundamental mechanism governing the switch of cells from an epithelial to a motile mesenchymal-like state. This transdifferentiation is regulated by key transcription factors, including Slug. The stability and function of Slug can be regulated by multiple mechanisms, including ubiquitin-mediated post-translational modifications. Here, by using a genome wide siRNA screen for human deubiquitinating enzymes (DUBs), we identified USP10 as a deubiquitinase for Slug in cancer cells...
May 24, 2018: Biochemical and Biophysical Research Communications
Yan Chen, Xumei Pang, Lijuan Ji, Yingchun Sun, Yongjing Ji
BACKGROUND Ubiquitin-specific peptidase 33 (USP33) is a deubiquitinase that balances the ubiquitin status of proteins. It has been reported to act as a tumor suppressor in colorectal cancer and lung cancer. However, the expression pattern and clinical significance of USP33 have not been investigated in gastric adenocarcinoma (GAC). MATERIAL AND METHODS We explored the USP33 protein and RNA levels by immunohistochemistry (IHC), Western blot analysis, and qRT-PCR. The Pearson chi-square test was performed to evaluate the statistical associations between USP33 level and patient characteristics...
May 26, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Qian Feng, Ying Miao, Jun Ge, Yukang Yuan, Yibo Zuo, Liping Qian, Jin Liu, Qiao Cheng, Tingting Guo, Liting Zhang, Zhengyuan Yu, Hui Zheng
Ataxin-3 (ATXN3) belongs to the Josephin family of deubiquitinases. So far, ATXN3 is majorly linked to the neurodegenerative disease, Machado-Joseph disease. The role of ATXN3 in the antiviral function has not been explored, and the in vivo deubiquitinating activity of ATXN3 remains largely unknown. In this study, we report that ATXN3 is an important positive regulator of type I IFN (IFN-I)-mediated antiviral activity in murine primary lung cells and human epithelial and fibroblast cell lines. We clarify that ATXN3 does not promote IFN-I production, but enhances the IFN-I-mediated signaling pathway...
May 25, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Anna De Blasio, Renza Vento, Riccardo Di Fiore
The Bcl-2 family, which plays important roles in controlling cancer development, is divided into antiapoptotic and proapoptotic members. The change in the balance between these members governs the life and death of the cells. Mcl-1 is an antiapoptotic member of this family and its distribution in normal and cancerous tissues strongly differs from that of Bcl-2. In human cancers, where upregulation of antiapoptotic proteins is common, Mcl-1 expression is regulated independent of Bcl-2 and its inhibition promotes senescence, a major barrier to tumorigenesis...
May 24, 2018: Journal of Cellular Physiology
Dheeraj Soni, Dong-Mei Wang, Sushil C Regmi, Manish Mittal, Stephen M Vogel, Dirk Schlüter, Chinnaswamy Tiruppathi
Vascular endothelial cadherin (VE-cad) expression at endothelial adherens junctions (AJs) regulates vascular homeostasis. Here we show that endothelial A20 is required for VE-cad expression at AJs to maintain and repair the injured endothelial barrier. In endothelial cell (EC)-restricted Tnfaip3 (A20) knockout ( A20 ∆EC ) mice, LPS challenge caused uncontrolled lung vascular leak and persistent sequestration of polymorphonuclear neutrophil (PMNs). Importantly, A20 ∆EC mice exhibited drastically reduced VE-cad expression in lungs compared with wild-type counterparts...
2018: Cell Death Discovery
Muyu Xu, James J Moresco, Max Chang, Amey Mukim, Davey Smith, Jolene K Diedrich, John R Yates, Katherine A Jones
HIV-1 Tat is a key regulator of viral transcription, however little is known about the mechanisms that control its turnover in T cells. Here we use a novel proteomics technique, called DiffPOP, to identify the molecular target of JIB-04, a small molecule compound that potently and selectively blocks HIV-1 Tat expression, transactivation, and virus replication in T cell lines. Mass-spectrometry analysis of whole-cell extracts from 2D10 Jurkat T cells revealed that JIB-04 targets Serine Hydroxymethyltransferase 2 (SHMT2), a regulator of glycine biosynthesis and an adaptor for the BRCC36 K63Ub-specific deubiquitinase in the BRISC complex...
May 2018: PLoS Pathogens
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
Lu Wang, Zibo Zhao, Patrick A Ozark, Damiano Fantini, Stacy A Marshall, Emily J Rendleman, Kira A Cozzolino, Nundia Louis, Xingyao He, Marc A Morgan, Yoh-Hei Takahashi, Clayton K Collings, Edwin R Smith, Panagiotis Ntziachristos, Jeffrey N Savas, Lihua Zou, Rintaro Hashizume, Joshua J Meeks, Ali Shilatifard
The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1...
May 21, 2018: Nature Medicine
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