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Deubiquitination

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https://www.readbyqxmd.com/read/28542609/potent-and-selective-inhibition-of-pathogenic-viruses-by-engineered-ubiquitin-variants
#1
Wei Zhang, Ben A Bailey-Elkin, Robert C M Knaap, Baldeep Khare, Tim J Dalebout, Garrett G Johnson, Puck B van Kasteren, Nigel J McLeish, Jun Gu, Wenguang He, Marjolein Kikkert, Brian L Mark, Sachdev S Sidhu
The recent Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola and Zika virus outbreaks exemplify the continued threat of (re-)emerging viruses to human health, and our inability to rapidly develop effective therapeutic countermeasures. Many viruses, including MERS-CoV and the Crimean-Congo hemorrhagic fever virus (CCHFV) encode deubiquitinating (DUB) enzymes that are critical for viral replication and pathogenicity. They bind and remove ubiquitin (Ub) and interferon stimulated gene 15 (ISG15) from cellular proteins to suppress host antiviral innate immune responses...
May 18, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28540657/uch-l1-inhibition-suppresses-tau-aggresome-formation-during-proteasomal-impairment
#2
Quntao Yu, Hongmao Zhang, Yuan Li, Chao Liu, Shaohui Wang, Xiaomei Liao
In conditions of proteasomal impairment, the damaged or misfolded proteins, collectively known as aggresome, can accumulate in the perinuclear space and be subsequently eliminated by autophagy. Abnormal aggregation of microtubule-associated protein tau in the cytoplasm is a common neuropathological feature of tauopathies. The deficiency in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a proteasomal deubiquitinating enzyme, is closely related to tau aggregation; however, the associated mechanisms remain unclear...
May 24, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28536288/cnot4-mediated-ubiquitination-of-influenza-a-virus-nucleoprotein-promotes-viral-rna-replication
#3
Yu-Chen Lin, King-Song Jeng, Michael M C Lai
Influenza A virus (IAV) RNA segments are individually packaged with viral nucleoprotein (NP) and RNA polymerases to form a viral ribonucleoprotein (vRNP) complex. We previously reported that NP is a monoubiquitinated protein which can be deubiquitinated by a cellular ubiquitin protease, USP11. In this study, we identified an E3 ubiquitin ligase, CNOT4 (Ccr4-Not transcription complex subunit 4), which can ubiquitinate NP. We found that the levels of viral RNA, protein, viral particles, and RNA polymerase activity in CNOT4 knockdown cells were lower than those in the control cells upon IAV infection...
May 23, 2017: MBio
https://www.readbyqxmd.com/read/28536144/the-deubiquitinating-enzymes-ubp12-and-ubp13-positively-regulate-myc2-levels-in-jasmonate-responses
#4
Jin Seo Jeong, Choonkyun Jung, Jun Sung Seo, Ju-Kon Kim, Nam-Hai Chua
The transcription factor MYC2 has emerged as a master regulator of jasmonate-mediated responses as well as cross-talk among different signaling pathways. The instability of MYC2 is in part due to the action of PUB10 E3 ligase, which can polyubiquitinate this protein. Here, we show that polyubiquitinated MYC2 can be deubiquitinated by UBP12 and UBP13 in vitro, suggesting that the two deubiquitinating enzymes can counteract the effect of PUB10 in vivo. Consistent with this view, UBP12 and UBP13 associate with MYC2 in the nucleus...
May 23, 2017: Plant Cell
https://www.readbyqxmd.com/read/28534493/usp13-negatively-regulates-antiviral-responses-by-deubiquitinating-sting
#5
He Sun, Qiang Zhang, Ying-Ying Jing, Man Zhang, Hai-Ying Wang, Zeng Cai, Tianzi Liuyu, Zhi-Dong Zhang, Tian-Chen Xiong, Yan Wu, Qi-Yun Zhu, Jing Yao, Hong-Bing Shu, Dandan Lin, Bo Zhong
STING (also known as MITA) is critical for host defence against viruses and the activity of STING is regulated by ubiquitination. However, the deubiquitination of STING is not fully understood. Here, we show that ubiquitin-specific protease 13 (USP13) is a STING-interacting protein that catalyses deubiquitination of STING. Knockdown or knockout of USP13 potentiates activation of IRF3 and NF-κB and expression of downstream genes after HSV-1 infection or transfection of DNA ligands. USP13 deficiency results in impaired replication of HSV-1...
May 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28520534/cpg-island-methylation-correlates-with-the-use-of-alternative-promoter-for-usp44-gene-expression-in-human-pluripotent-stem-cells-and-testis
#6
Philippe Tropel, Laura Jung, Cécile André, Adeline Ndandougou, Stéphane Viville
Deubiquitinating enzymes may play a major regulatory role in pluripotent stem cells (PSCs) but few studies have investigated this topic. Within this family of enzymes, we found that the ubiquitin specific peptidase, USP44, is highly expressed in embryonic stem cells, induced PSCs and testes as compared to differentiated progenies and somatic organs. Analysis by qPCR and 5'RACE showed that alternate promoters are responsible for expression in PSCs and organs. We noticed 7 regions of transcription initiation, some of them with cell- or tissue-specific activity...
May 18, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28509417/overexpression-of-ubiquitin-specific-peptidase-14-predicts-unfavorable-prognosis-in-esophageal-squamous-cell-carcinoma
#7
Baozhu Zhang, Mengqing Li, Pinzhu Huang, Xin-Yuan Guan, Ying-Hui Zhu
BACKGROUND: Ubiquitin specific peptidase 14 (USP14), a deubiquitinating enzyme, has been documented as a key element to regulate the proteolysis function of proteasomes and an attractive therapeutic target for several cancers. Herein, we elucidate the role of USP14 in predicting the prognosis of patients with esophageal squamous cell carcinoma (ESCC). METHODS: USP14 expression was detected in ESCC tissues and matched adjacent non-tumorous tissues by quantitative real-time reverse transcription-PCR and immunohistochemistry...
May 16, 2017: Thoracic Cancer
https://www.readbyqxmd.com/read/28505193/the-drosophila-orthologue-of-the-int6-onco-protein-regulates-mitotic-microtubule-growth-and-kinetochore-structure
#8
Fioranna Renda, Claudia Pellacani, Anton Strunov, Elisabetta Bucciarelli, Valeria Naim, Giuseppe Bosso, Elena Kiseleva, Silvia Bonaccorsi, David J Sharp, Alexey Khodjakov, Maurizio Gatti, Maria Patrizia Somma
INT6/eIF3e is a highly conserved component of the translation initiation complex that interacts with both the 26S proteasome and the COP9 signalosome, two complexes implicated in ubiquitin-mediated protein degradation. The INT6 gene was originally identified as the insertion site of the mouse mammary tumor virus (MMTV), and later shown to be involved in human tumorigenesis. Here we show that depletion of the Drosophila orthologue of INT6 (Int6) results in short mitotic spindles and deformed centromeres and kinetochores with low intra-kinetochore distance...
May 15, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28500221/ubiquitin-c-terminal-hydrolase-l1-uch-l1-promotes-hippocampus-dependent-memory-via-its-deubiquitinating-effect-on-trkb
#9
Yun-Yun Guo, Lu Yi, Yuan Zheng, Xiao-Rong Chen, Jun-Lu Dong, Rong-Rong Yuan, Shu-Hong Huang, Hui Yu, Yue Wang, Zhe-Yu Chen, Bo Su
Multiple studies have established that brain-derived neurotrophic factor (BDNF) plays a critical role in the regulation of synaptic plasticity via its receptor TrkB. In addition to being phosphorylated, TrkB has also been demonstrated to be ubiquitinated. However, the mechanisms of TrkB ubiquitination and its biological functions remain poorly understood. In this study, we demonstrate that ubiquitin C-terminal hydrolase L1 (UCH-L1) promotes contextual fear conditioning (CFC) learning and memory via the regulation of ubiquitination of TrkB...
May 12, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28499884/inhibition-of-ubiquitin-specific-protease-34-usp34-induces-epithelial-mesenchymal-transition-and-promotes-stemness-in-mammary-epithelial-cells
#10
Eunhye Oh, Ji Young Kim, Daeil Sung, Youngkwan Cho, Nahyun Lee, Hyunsook An, Yoon-Jae Kim, Tae-Min Cho, Jae Hong Seo
Ubiquitin-specific protease 34 (USP34) is a deubiquitinating enzyme that regulates Axin stability and plays a critical role in Wnt/β-catenin signaling. We sought to investigate the role of USP34 on epithelial-mesenchymal (EMT) induction and its effects on mammary epithelial stem cells. USP34 expression levels were relatively lower in MDA-MB-231 and 4T1 mesenchymal-like cells when compared to epithelial-like cells. Inhibition of USP34 in NMuMG cells induced EMT, as evidenced by the upregulation of EMT markers including N-cadherin, phospho-Smad3, Snail and active-β-catenin, as well as the downregulation of Axin 1 and E-cadherin...
May 10, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28498859/usp9x-counteracts-differential-ubiquitination-of-nphp5-by-march7-and-bbs11-to-regulate-ciliogenesis
#11
Arindam Das, Jin Qian, William Y Tsang
Ciliogenesis is a fundamental biological process central to human health. Precisely how this process is coordinated with the cell cycle remains an open question. We report that nephrocystin-5 (NPHP5/IQCB1), a positive regulator of ciliogenesis, is a stable and low turnover protein subjected to cycles of ubiquitination and deubiquitination. NPHP5 directly binds to a deubiquitinating enzyme USP9X/FAM and two E3 ubiquitin ligases BBS11/TRIM32 and MARCH7/axotrophin. NPHP5 undergoes K63 ubiquitination in a cell cycle dependent manner and K48/K63 ubiquitination upon USP9X depletion or inhibition...
May 12, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28498477/identification-of-candidate-substrates-of-ubiquitin-specific-protease-13-using-2d-dige
#12
Jianmin Wang, Yingli Liu, Lijuan Tang, Sufen Qi, Yingjun Mi, Dianwu Liu, Qingbao Tian
The present study aimed to identify candidate substrates of ubiquitin-specific protease (USP)13 using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). USP13 is a well-characterized member of the USP family, which regulates diverse cellular functions by cleaving ubiquitin from ubiquitinated protein substrates. However, existing studies indicate that USP13 has no detectable hydrolytic activity in vitro. This finding implies that USP13 likely has different substrate specificity. In this study, a USP cleavage assay was performed using two different types of model substrates (glutathione S-transferase-Ub52 and ubiquitin-β-galactosidase) to detect the deubiquitinating enzyme (DUB) activity of USP13...
May 10, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28493408/monoubiquitination-joins-polyubiquitination-as-an-esteemed-proteasomal-targeting-signal
#13
REVIEW
Ido Livneh, Yelena Kravtsova-Ivantsiv, Ori Braten, Yong Tae Kwon, Aaron Ciechanover
A polyubiquitin chain attached covalently to the target substrate has been recognized for long as the "canonical" proteasomal degradation signal. However, several proteins have been shown to be targeted for degradation following monoubiquitination, indicating that the proteasome can recognize signals other than a ubiquitin polymer. A comprehensive screen aiming at determining the extent of this mode of recognition revealed that ∼40% of mammalian and ∼20% of yeast proteins are degraded following monoubiquitination...
June 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28492230/targeting-the-deubiquitinase-stambp-inhibits-nalp7-inflammasome-activity
#14
Joseph S Bednash, Nathaniel Weathington, James Londino, Mauricio Rojas, Dexter L Gulick, Robert Fort, SeungHye Han, Alison C McKelvey, Bill B Chen, Rama K Mallampalli
Inflammasomes regulate innate immune responses by facilitating maturation of inflammatory cytokines, interleukin (IL)-1β and IL-18. NACHT, LRR and PYD domains-containing protein 7 (NALP7) is one inflammasome constituent, but little is known about its cellular handling. Here we show a mechanism for NALP7 protein stabilization and activation of the inflammasome by Toll-like receptor (TLR) agonism with bacterial lipopolysaccharide (LPS) and the synthetic acylated lipopeptide Pam3CSK4. NALP7 is constitutively ubiquitinated and recruited to the endolysosome for degradation...
May 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28490584/a-naturally-occurring-recombinant-enterovirus-expresses-a-torovirus-deubiquitinase
#15
Pengcheng Shang, Saurav Misra, Ben Hause, Ying Fang
Enteroviruses are implicated in a wide range of diseases in human and animals. In this study, a novel enterovirus (species G; EVG 08/NC_USA/2015) was isolated from a diagnostic sample of neonatal pig diarrhea case and identified using metagenomics and complete genome sequencing. The viral genome shares 75.4% nucleotide identity with a prototypic EVG strain (PEV9 UKG/410/73). Remarkably, a 582 nucleotide insertion, flanked by 3C(pro) cleavage sites at 5' - and 3' - ends, was found in the 2C/3A junction region of the viral genome...
May 10, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28484036/bam-dependent-deubiquitinase-complex-can-disrupt-germ-line-stem-cell-maintenance-by-targeting-cyclin-a
#16
Shanming Ji, Chaoyi Li, Lin Hu, Kehui Liu, Jie Mei, Yuewan Luo, Yi Tao, Zongping Xia, Qinmiao Sun, Dahua Chen
Drosophila germ-line stem cells (GSCs) provide an excellent model to study the regulatory mechanisms of stem cells in vivo. Bag of marbles (bam) has been demonstrated to be necessary and sufficient to promote GSC and cystoblast differentiation. Despite extensive investigation of its regulation and genetic functions, the biochemical nature of the Bam protein has been unknown. Here, we report that Bam is an ubiquitin-associated protein and controls the turnover of cyclin A (CycA). Mechanistically, we found that Bam associated with Otu to form a deubiquitinase complex that stabilized CycA by deubiquitination, thus providing a mechanism to explain how ectopic expression of Bam in GSCs promotes differentiation...
May 8, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28483520/pppde1-is-a-novel-deubiquitinase-belonging-to-a-cysteine-isopeptidase-family
#17
Xingwang Xie, Xueyan Wang, Dong Jiang, Jianghua Wang, Ran Fei, Xu Cong, Lai Wei, Yu Wang, Hongsong Chen
Ubiquitinlation of proteins is prevalent and important in both normal and pathological cellular processes. Deubiquitinating enzymes (DUBs) can remove the ubiquitin tags on substrate proteins and dynamically regulate the ubiquitination process. The PPPDE family proteins were predicted to be a novel class of deubiquitinating peptidase, but this has not yet been experimentally proved. Here we validated the deubiquitinating activity of PPPDE1 and revealed its isopeptidase activity against ubiquitin conjugated through Lys 48 and Lys 63...
May 5, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28476940/mechanisms-of-regulation-and-diversification-of-deubiquitylating-enzyme-function
#18
REVIEW
Pawel Leznicki, Yogesh Kulathu
Deubiquitylating (or deubiquitinating) enzymes (DUBs) are proteases that reverse protein ubiquitylation and therefore modulate the outcome of this post-translational modification. DUBs regulate a variety of intracellular processes, including protein turnover, signalling pathways and the DNA damage response. They have also been linked to a number of human diseases, such as cancer, and inflammatory and neurodegenerative disorders. Although we are beginning to better appreciate the role of DUBs in basic cell biology and their importance for human health, there are still many unknowns...
May 5, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28475871/aging-triggers-cytoplasmic-depletion-and-nuclear-translocation-of-the-e3-ligase-mahogunin-a%C3%A2-function-for-ubiquitin-in-neuronal-survival
#19
Stefano Benvegnù, María Inés Mateo, Ernest Palomer, Jerónimo Jurado-Arjona, Carlos G Dotti
A decline in proteasome function is causally connected to neuronal aging and aging-associated neuropathologies. By using hippocampal neurons in culture and in vivo, we show that aging triggers a reduction and a cytoplasm-to-nucleus redistribution of the E3 ubiquitin ligase mahogunin (MGRN1). Proteasome impairment induces MGRN1 monoubiquitination, the key post-translational modification for its nuclear entry. One potential mechanism for MGRN1 monoubiquitination is via progressive deubiquitination at the proteasome of polyubiquitinated MGRN1...
May 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28475174/diverse-ubiquitin-linkages-regulate-rip-kinases-mediated-inflammatory-and-cell-death-signaling
#20
REVIEW
Axel Witt, Domagoj Vucic
Members of the RIP kinase family are key regulators of inflammation and cell death signaling implicated in maintaining immune responses and proper tissue homeostasis. Increasing evidence points to post-translational modifications of RIP1, RIP2 and RIP3 as being critical for regulating their function. Ubiquitination and the E3 ligases, such as inhibitors of apoptosis (IAP) proteins and LUBAC, that direct substrate selectivity as well as the deubiquitinating enzymes, such as A20 and OTULIN, that reverse these modifications dictate the outcome of RIP kinase signaling...
May 5, 2017: Cell Death and Differentiation
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