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ubiquitin ligase

Toshiyuki Araki, Shuji Wakatsuki
ZNRF1 is an E3 ubiquitin ligase constitutively expressed in almost all neurons in the central and peripheral nervous systems during development and in adulthood. From this expression profile, the role of ZNRF1 is assumed to be common to many different types of neurons. We have analyzed the roles of ZNRF1-dependent degradation of target proteins in neurons. In mature neurons, ZNRF1 is activated in response to different types of stress that cause neuronal/axonal degeneration, and degrade AKT to activate GSK3B...
August 14, 2018: Neuroscience Research
Yu-Hui Li, Ming Zhong, Hong-Liang Zang, Xiao-Feng Tian
Ninety percent of all cancer related deaths happen due to metastatic progression. One important protein facilitating metastatic progression in hepatocellular carcinoma (HCC) is the metastasis associated 1 protein (MTA-1). We have earlier shown that in the context of HCC and normal liver cell lines, HuH6 and THLE-2, respectively. MTA-1 protein is actively stabilized in HCC cell lines and actively degraded in normal liver cells. We had also shown that TRIM25 is the E3 ligase that interacts with and degrades MTA-1 protein in normal liver cells...
August 14, 2018: Experimental Cell Research
Bennett H Penn, Zoe Netter, Jeffrey R Johnson, John Von Dollen, Gwendolyn M Jang, Tasha Johnson, Yamini M Ohol, Cyrus Maher, Samantha L Bell, Kristina Geiger, Guillaume Golovkine, Xiaotang Du, Alex Choi, Trevor Parry, Bhopal C Mohapatra, Matthew D Storck, Hamid Band, Chen Chen, Stefanie Jäger, Michael Shales, Dan A Portnoy, Ryan Hernandez, Laurent Coscoy, Jeffery S Cox, Nevan J Krogan
Although macrophages are armed with potent antibacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage intrinsic bacterial control, and the Mtb strategies to overcome them, are poorly understood. To further study these processes, we used an affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two factors involved in Mtb pathogenesis-the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL...
August 16, 2018: Molecular Cell
Yuliang Tan, Chunyu Jin, Wubin Ma, Yiren Hu, Bogdan Tanasa, Soohwan Oh, Amir Gamliel, Qi Ma, Lu Yao, Jie Zhang, Kenny Ohgi, Wen Liu, Aneel K Aggarwal, Michael G Rosenfeld
Nuclear receptors induce both transcriptional activation and repression programs responsible for development, homeostasis, and disease. Here, we report a previously overlooked enhancer decommissioning strategy underlying a large estrogen receptor alpha (ERα)-dependent transcriptional repression program. The unexpected signature for this E2 -induced program resides in indirect recruitment of ERα to a large cohort of pioneer factor basally active FOXA1-bound enhancers that lack cognate ERα DNA-binding elements...
August 16, 2018: Molecular Cell
Christian Steinebach, Stefanie Lindner, Namrata D Udeshi, Deepak C Mani, Hannes Kehm, Simon Köpff, Steven A Carr, Michael Gütschow, Jan Kronke
The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide, all approved for the treatment of multiple myeloma, induce targeted ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3) via the cereblon (CRBN) E3 ubiquitin ligase. IMiD-based proteolysis targeting chimeras (PROTACs) can efficiently recruit CRBN to a protein of interest leading to its ubiquitination and proteasomal degradation. By linking two pomalidomide molecules, we designed homobifunctional, so-called Homo-PROTACs and investigated their ability to induce self-directed ubiquitination and degradation...
August 17, 2018: ACS Chemical Biology
Jorge Vicente, Guillermina M Mendiondo, Jarne Pauwels, Victoria Pastor, Yovanny Izquierdo, Christin Naumann, Mahsa Movahedi, Daniel Rooney, Daniel J Gibbs, Katherine Smart, Andreas Bachmair, Julie E Gray, Nico Dissmeyer, Carmen Castresana, Rumiana V Ray, Kris Gevaert, Michael J Holdsworth
The N-end rule pathway is a highly conserved constituent of the ubiquitin proteasome system, yet little is known about its biological roles. Here we explored the role of the N-end rule pathway in the plant immune response. We investigated the genetic influences of components of the pathway and known protein substrates on physiological, biochemical and metabolic responses to pathogen infection. We show that the glutamine (Gln) deamidation and cysteine (Cys) oxidation branches are both components of the plant immune system, through the E3 ligase PROTEOLYSIS (PRT)6...
August 17, 2018: New Phytologist
Praveen Koganti, Gal Levy-Cohen, Michael Blank
Protein ubiquitination is an evolutionary conserved highly-orchestrated enzymatic cascade essential for normal cellular functions and homeostasis maintenance. This pathway relies on a defined set of cellular enzymes, among them, substrate-specific E3 ubiquitin ligases (E3s). These ligases are the most critical players, as they define the spatiotemporal nature of ubiquitination and confer specificity to this cascade. Smurf1 and Smurf2 (Smurfs) are the C2-WW-HECT-domain E3 ubiquitin ligases, which recently emerged as important determinants of pivotal cellular processes...
2018: Frontiers in Oncology
Wei Wu, Li Nie, Li Zhang, Yan Li
Background: Oncogenic Notch1 is known to activate the NF-κB pathway in T cell acute lymphoblastic leukemia (T-ALL) and to up-regulate the transcription of Asb2α, a specificity factor for an E3 ubiquitin ligase complex that plays an important role in hematopoietic differentiation. Therefore, we hypothesize that Notch1 might regulate the NF-κB pathway through Asb2α. Methods: The study involved down-regulation of Notch1 in T-ALL cell lines (CCRF-CEM cells and MOLT-4 cells) through treatment with gamma-secretase inhibitor (GSI) as well as the modulation of Asb2 in CCRF-CEM cells and MOLT-4 cells through transduction with lentivirus carrying Asb2 or Asb2 -shRNA...
2018: Cellular & Molecular Biology Letters
Gabriel Keeble-Gagnère, Philippe Rigault, Josquin Tibbits, Raj Pasam, Matthew Hayden, Kerrie Forrest, Zeev Frenkel, Abraham Korol, B Emma Huang, Colin Cavanagh, Jen Taylor, Michael Abrouk, Andrew Sharpe, David Konkin, Pierre Sourdille, Benoît Darrier, Frédéric Choulet, Aurélien Bernard, Simone Rochfort, Adam Dimech, Nathan Watson-Haigh, Ute Baumann, Paul Eckermann, Delphine Fleury, Angela Juhasz, Sébastien Boisvert, Marc-Alexandre Nolin, Jaroslav Doležel, Hana Šimková, Helena Toegelová, Jan Šafář, Ming-Cheng Luo, Francisco Câmara, Matthias Pfeifer, Don Isdale, Johan Nyström-Persson, Iwgsc, Dal-Hoe Koo, Matthew Tinning, Dangqun Cui, Zhengang Ru, Rudi Appels
BACKGROUND: Numerous scaffold-level sequences for wheat are now being released and, in this context, we report on a strategy for improving the overall assembly to a level comparable to that of the human genome. RESULTS: Using chromosome 7A of wheat as a model, sequence-finished megabase-scale sections of this chromosome were established by combining a new independent assembly using a bacterial artificial chromosome (BAC)-based physical map, BAC pool paired-end sequencing, chromosome-arm-specific mate-pair sequencing and Bionano optical mapping with the International Wheat Genome Sequencing Consortium RefSeq v1...
August 17, 2018: Genome Biology
Kotaro Soji, Shigehiro Doi, Ayumu Nakashima, Kensuke Sasaki, Toshiki Doi, Takao Masaki
Deubiquitinating enzymes (DUBs) remove ubiquitin from their substrates and, together with ubiquitin ligases, play an important role in the regulation of protein expression. Although transforming growth factor (TGF)-β1-Smad signaling is a central pathway of renal fibrosis, the role of DUBs in the expression of TGF-β receptors and Smads during the development of renal fibrosis remains unknown. In this study, we investigated whether PR-619, a pan-DUB inhibitor, suppresses fibrosis in mice with unilateral ureteral obstruction (UUO) and TGF-β1-stimulated normal rat kidney (NRK)-49F cells, a rat renal fibroblast cell line...
2018: PloS One
Elizabeth A Whitcomb, Yien Che Tsai, Johnvesly Basappa, Ke Liu, Aurélie K Le Feuvre, Allan M Weissman, Allen Taylor
Ubiquitinylation drives many cellular processes by targeting proteins for proteasomal degradation. Ubiquitin conjugation enzymes promote ubiquitinylation and, thus, degradation of protein substrates. Ubiquitinylation is a well-known posttranslational modification controlling cell-cycle transitions and levels or/and activation levels of ubiquitin-conjugating enzymes change during development and cell cycle. Progression through the cell cycle is tightly controlled by CDK inhibitors such as p27Kip1 . Here we show that, in contrast to promoting its degradation, the ubiquitin-conjugating enzyme UBCH7/UBE2L3 specifically protects p27Kip1 from degradation...
August 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Jon P Day, Ellanor Whiteley, Michael Freeley, Aideen Long, Beatrice Malacrida, Patrick Kiely, George S Baillie
Aim: RACK1 is a multifunctional scaffolding protein that is expressed in many cellular compartments, orchestrating a number of signaling processes. RACK1 acts as a signaling hub to localize active enzymes to discrete locations; therefore tight control of RACK1 is vital to cellular homeostasis. Our aim was to identify the mechanisms responsible for RACK1 turnover and show that degradation is directed by the ubiquitin proteasome system. Results: Using siRNA screening, we identified RAB40C as the ubiquitin E3 ligase responsible for ubiquitination of RACK1, and that the action of RAB40C in controlling RACK1 levels is crucial to both cancer cell growth and migration of T cells...
July 2018: Future Science OA
Robert F H Walter, Robert Werner, Michael Wessolly, Elena Mairinger, Sabrina Borchert, Jan Schmeller, Jens Kollmeier, Thomas Mairinger, Thomas Hager, Agnes Bankfalvi, Daniel C Christoph, Wilfried E E Eberhardt, Till Plönes, Clemens Aigner, Kurt W Schmid, Jeremias Wohlschlaeger, Fabian D Mairinger
Previously, our group demonstrated that nuclear expression of E3 ubiquitin ligase (MDM2) in malignant pleural mesothelioma (MPM) is significantly associated with decreased overall survival. A possible explanation may be that overexpression of MDM2 leads to a proteasomal degradation of TP53 that eventually results in a loss of TP53-induced apoptosis and senescence. It is well known from other tumor entities that restoration of TP53 activity, e.g., by MDM2 inhibition, results in an instant TP53-induced stress and/or DNA damage response of cancer cells...
2018: Journal of Oncology
Yanan Zhao, Xuezhi Cao, Mingzhe Guo, Xuesong Wang, Tao Yu, Liqing Ye, Lin Han, Lei Hei, Wanyin Tao, Yimin Tong, Yongfen Xu, Jin Zhong
Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. HCV can be sensed by host innate immunity to induce expression of interferons (IFNs) and a number of antiviral effectors. In this study, we found HCV infection induced the expression of Neuralized E3 Ubiquitin Protein Ligase 3 (NEURL3), a putative E3 ligase, in a manner that requires the involvement of innate immune sensing but is independent of the IFN action. Furthermore, we showed that NEURL3 inhibited HCV infection, while had little effect on other RNA viruses including zika virus, dengue virus and vesicular stomatitis virus...
August 15, 2018: Journal of Virology
Yin-Li Zhang, Long-Wen Zhao, Jue Zhang, Rongrong Le, Shu-Yan Ji, Chuan Chen, Yawei Gao, Dali Li, Shaorong Gao, Heng-Yu Fan
Mammalian oocytes and zygotes have the unique ability to reprogram a somatic cell nucleus into a totipotent state. SUV39H1/2-mediated histone H3 lysine-9 trimethylation (H3K9me3) is a major barrier to efficient reprogramming. How SUV39H1/2 activities are regulated in early embryos and during generation of induced pluripotent stem cells (iPSCs) remains unclear. Since expression of the CRL4 E3 ubiquitin ligase in oocytes is crucial for female fertility, we analyzed putative CRL4 adaptors (DCAFs) and identified DCAF13 as a novel CRL4 adaptor that is essential for preimplantation embryonic development...
August 14, 2018: EMBO Journal
Wen-Jing Fan, Zhi-Qiao Fan, Mei-Juan Yang, Yao-Zhu Pan, Hai Bai
Cereblon(CRBN) is a brain-associated protein with ionic protease activity, which interacts with DNA damage-binding protein-1 (DDB1), Cullin 4 (Cul4A or Cul4B), and regulator of Cullins 1 (RoC1) to form the functional E3 ubiquitin ligase complex(CRBN-CRL4) that performs proteolysis via the ubiquitin-proteasome pathway. And CRBN is a necessary target protein for the anti-myeloma effect of immunomodulators. The combination of lenalidomide and CRBN recruited a new substrate that binds to the CRBN-CRL4 complex, leading to increased ubiquitination and proteasome-dependent degradation, thus resulting in anti-myeloma activity...
August 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Eugene Oh, David Akopian, Michael Rape
Ubiquitylation is an essential posttranslational modification that controls cell division, differentiation, and survival in all eukaryotes. By combining multiple E3 ligases (writers), ubiquitin-binding effectors (readers), and deubiquitylases (erasers) with functionally distinct ubiquitylation tags, the ubiquitin system constitutes a powerful signaling network that is employed in similar ways from yeast to humans. Here, we discuss conserved principles of ubiquitin-dependent signaling that illustrate how this posttranslational modification shapes intracellular signaling networks to establish robust development and homeostasis throughout the eukaryotic kingdom...
August 15, 2018: Annual Review of Cell and Developmental Biology
Olga Fedorova, Alexandra Daks, Varvara Petrova, Alexey Petukhov, Larissa Lezina, Oleg Shuvalov, Pavel Davidovich, Darya Kriger, Ekaterina Lomert, Dmitry Tentler, Victor Kartsev, Burhan Uyanik, Vyacheslav Tribulovich, Oleg Demidov, Gerry Melino, Nickolai A Barlev
The p53 protein is a key tumor suppressor in mammals. In response to various forms of genotoxic stress p53 stimulates expression of genes whose products induce cell cycle arrest and/or apoptosis. An E3-ubiquitin ligase, Mdm2 (mouse-double-minute 2) and its human ortholog Hdm2, physically interact with the amino-terminus of p53 to mediate its ubiquitin-mediated degradation via the proteasome. Thus, pharmacological inhibition of the p53-Mdm2 interaction leads to overall stabilization of p53 and stimulation of its anti-tumorigenic activity...
August 15, 2018: Cell Cycle
Lea Lough, Dan Sherman, Eric Ni, Lauren M Young, Bing Hao, Timothy Cardozo
Skp2 is a member of the F-box family of proteins that serve as substrate-specific adaptors in Skp1-CUL1-ROC1-F-box (SCF) E3 ubiquitin ligases. Skp2 (Fbxl1) directly binds to the tumor suppressor p27 in the context of the SCFSkp2 E3 ubiquitin ligase to ubiquitylate and target-phosphorylated p27 for proteasomal degradation. As p27 is a powerful suppressor of growth in a variety of cells, and as Skp2 is also overexpressed in many human cancers, Skp2 is considered an oncogene and an intriguing drug target. However, despite 20 years of investigation, a valid chemical inhibitor of Skp2-mediated degradation of p27 has not been identified...
July 1, 2018: MedChemComm
Sirish K Ippagunta, Julie A Pollock, Naina Sharma, Wenwei Lin, Taosheng Chen, Kazuki Tawaratsumida, Anthony A High, Jaeki Min, Yizhe Chen, R Kiplin Guy, Vanessa Redecke, John A Katzenellenbogen, Hans Häcker
Toll-like receptors (TLRs) recognize various pathogen- and host tissue-derived molecules and initiate inflammatory immune responses. Exaggerated or prolonged TLR activation, however, can lead to etiologically diverse diseases, such as bacterial sepsis, metabolic and autoimmune diseases, or stroke. Despite the apparent medical need, no small-molecule drugs against TLR pathways are clinically available. This may be because of the complex signaling mechanisms of TLRs, which are governed by a series of protein-protein interactions initiated by Toll/interleukin-1 receptor homology domains (TIR) found in TLRs and the cytoplasmic adaptor proteins TIRAP and MyD88...
August 14, 2018: Science Signaling
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