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ubiquitin ligase

Jyoti Batra, Judd F Hultquist, Dandan Liu, Olena Shtanko, John Von Dollen, Laura Satkamp, Gwendolyn M Jang, Priya Luthra, Toni M Schwarz, Gabriel I Small, Eusondia Arnett, Manu Anantpadma, Ann Reyes, Daisy W Leung, Robyn Kaake, Paige Haas, Carson B Schmidt, Larry S Schlesinger, Douglas J LaCount, Robert A Davey, Gaya K Amarasinghe, Christopher F Basler, Nevan J Krogan
Ebola virus (EBOV) infection often results in fatal illness in humans, yet little is known about how EBOV usurps host pathways during infection. To address this, we used affinity tag-purification mass spectrometry (AP-MS) to generate an EBOV-host protein-protein interaction (PPI) map. We uncovered 194 high-confidence EBOV-human PPIs, including one between the viral transcription regulator VP30 and the host ubiquitin ligase RBBP6. Domain mapping identified a 23 amino acid region within RBBP6 that binds to VP30...
December 13, 2018: Cell
Pengfei Bai, Chan-Ho Park, Gautam Shirsekar, Pattavipha Songkumarn, Maria Bellizzi, Guo-Liang Wang
Magnaporthe oryzae is an important fungal pathogen of both rice and wheat. However, how M. oryzae effectors modulate plant immunity is not fully understood. Previous studies showed that the M. oryzae effector AvrPiz-t targets the host ubiquitin-proteasome system to manipulate plant defense. In return, two rice ubiquitin E3 ligases, APIP6 and APIP10, ubiquitinate AvrPiz-t for degradation. To determine how lysine residues contribute to AvrPiz-t stability and function, we generated double (K1,2R-AvrPiz-t), triple (K1,2,3R-AvrPiz-t) and lysine-free (LF-AvrPiz-t) mutants by mutating lysines into arginines in AvrPiz-t...
December 12, 2018: Molecular Plant Pathology
Hyunhee Joo, Chae Woo Lim, Sung Chul Lee
Plants have evolved complex defense mechanisms to adapt and survive under adverse growth conditions. Abscisic acid (ABA) is a phytohormone that plays a pivotal role in the stress response, especially regulation of the stomatal aperture in response to drought. Here, we identified the pepper CaASRF1 (Capsicum annuum ABA Sensitive RING Finger E3 ligase 1) gene, which modulates drought stress tolerance via ABA-mediated signalling. CaASRF1 contains a C3H2C3 type RING finger domain, which functions as an E3 ligase by attaching ubiquitins to the target proteins...
December 12, 2018: Plant Journal: for Cell and Molecular Biology
Maayan Korman, Yifat Elharar, Itzhak Fishov, Eyal Gur
AIM: Mycobacterium tuberculosis possesses an intracellular tagging and degradation system, which has emerged as a target for development of anti-tuberculosis agents. In this system, PafA is the ligase that marks proteins for degradation by their covalent modification with a protein modifier. Here, we studied pafA transcriptional regulation, which remained elusive despite its importance for M. tuberculosis virulence. MATERIALS & METHODS: Working with Mycobacterium smegmatis, a mycobacterial model organism, we examined the involvement of the global regulators PafB and PafC in pafA regulation...
December 14, 2018: Future Microbiology
Huili Li, Jing Zhang, Lee Niswander
Micronutrition is essential for neural tube closure, and zinc deficiency is associated with human neural tube defects. Here, we modeled zinc deficiency in mouse embryos, and used live imaging and molecular studies to determine how zinc deficiency affects neural tube closure. Embryos cultured with the zinc chelator TPEN failed to close the neural tube and showed excess apoptosis. TPEN-induced p53 protein stabilization in vivo and in neuroepithelial cell cultures and apoptosis was dependent on p53. Mechanistically, zinc deficiency resulted in disrupted interaction between p53 and the zinc-dependent E3 ubiquitin ligase Mdm2, and greatly reduced p53 ubiquitylation...
December 13, 2018: Development
Ping Wee, Zhixiang Wang
The overactivation of epidermal growth factor (EGF) receptor (EGFR) is implicated in various cancers. Endocytosis plays an important role in EGFR-mediated cell signaling. We previously found that EGFR endocytosis during mitosis is mediated differently from interphase. While the regulation of EGFR endocytosis in interphase is well understood, little is known regarding the regulation of EGFR endocytosis during mitosis. Here, we found that contrary to interphase cells, mitotic EGFR endocytosis is more reliant on the activation of the E3 ligase CBL...
December 7, 2018: Cells
Sam A Menzies, Norbert Volkmar, Dick Jh van den Boomen, Richard T Timms, Anna S Dickson, James A Nathan, Paul J Lehner
Mammalian HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the cholesterol biosynthetic pathway and the therapeutic target of statins, is post-transcriptionally regulated by sterol-accelerated degradation. Under cholesterol-replete conditions, HMGCR is ubiquitinated and degraded, but the identity of the E3 ubiquitin ligase(s) responsible for mammalian HMGCR turnover remains controversial. Using systematic, unbiased CRISPR/Cas9 genome-wide screens with a sterol-sensitive endogenous HMGCR reporter, we comprehensively map the E3 ligase landscape required for sterol-accelerated HMGCR degradation...
December 13, 2018: ELife
Wei Wang, Han Du, Huiping Liu, Fangfang Hu, Guangzhi Liu
SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) serves a pivotal role in a variety of pathological processes and in tumor cell migration and invasion; however, its functional mechanism in ovarian cancer (OC) remains unknown. Previously, we observed overexpression of SMURF1 in OC tissues. In the present study, the role of SMURF1 in OC metastasis was investigated. The results revealed that SMURF1 was upregulated in OC cell lines of greater aggression than less aggressive cells. Downregulation of SMURF1 significantly inhibited OC cell invasion and migration, whereas upregulation of SMURF1 promoted OC cell invasion and migration...
October 31, 2018: Oncology Reports
Chao Wang, Genbin Shi, Xinhua Ji
The RING finger-dependent ubiquitin ligase (E3) gp78, known as the tumor autocrine motility factor receptor, contributes to tumor progression. The protein interacts with its cognate ubiquitin-conjugating enzyme (E2), Ube2g2, via its RING domain and a unique region called G2BR that strongly binds to E2. The binding of G2BR to Ube2g2 allosterically enhances the binding of RING to E2, and the binding of RING triggers the departure of G2BR from E2 also in an allosteric fashion. Targeting these allosteric events, we developed a family of inhibitors that irreversibly block E2-E3 interactions and thereby eliminate the tumorigenic effect of gp78...
November 1, 2018: MedChemComm
Rui Zhang, Jing-Jing Hong, Qiaoyun Yang, Chin-Tong Ong, Bo-An Li, Yih-Cherng Liou
Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification by which poly ADP-ribose (PAR) polymers are covalently added to proteins through a PAR polymerase (PARP). Here, using proteomic approach, we identify the transcriptional regulator, OVOL2, is a novel substrate of PARP1 and can be PARylated at residues Lysine 145, Lysine 176, and Lysine 212 within its C2H2 zinc finger domains. Overexpression of PARylated OVOL2 alters cell morphology and induces lagging chromosomes and aneuploidy. To define the underlying molecular mechanism by which OVOL2 induces abnormal cell cycle and centrosome amplification, we uncover that the OVOL2 elevates the protein levels of Cyclin E by enhancing its stability...
December 12, 2018: Oncogene
Vittoria Zoppi, Scott J Hughes, Chiara Maniaci, Andrea Testa, Teresa Gmaschitz, Corinna Wieshofer, Manfred Koegl, Kristin Riching, Danette L Daniels, Andrea Spallarossa, Alessio Ciulli
Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be a lengthy and unpredictable process, and it remains unclear whether any combination of E3 and target might be productive for degradation. We describe a probe-quality degrader for a ligase-target pair deemed unsuitable: the von Hippel-Lindau (VHL) and BRD9, a bromodomain-containing subunit of the SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could be optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns and linkers, and monitoring cellular degradation activities, kinetic profiles, and ubiquitination, as well as ternary complex formation thermodynamics...
December 12, 2018: Journal of Medicinal Chemistry
Nathan H Roy, Joanna L MacKay, Tanner F Robertson, Daniel A Hammer, Janis K Burkhardt
T cell entry into inflamed tissue involves firm adhesion, spreading, and migration of the T cells across endothelial barriers. These events depend on "outside-in" signals through which engaged integrins direct cytoskeletal reorganization. We investigated the molecular events that mediate this process and found that T cells from mice lacking expression of the adaptor protein Crk exhibited defects in phenotypes induced by the integrin lymphocyte function-associated antigen 1 (LFA-1), namely, actin polymerization, leading edge formation, and two-dimensional cell migration...
December 11, 2018: Science Signaling
Veronika Kinterova, Jiri Kanka, Petruskova Veronika, Tereza Toralova
The mechanism of maternal protein degradation during preimplantation development has not been clarified yet. It is thought that a lot of maternal proteins are degraded by ubiquitin-proteasome system. In this study, we focused on the role of the SCF (Skp1-Cullin-F-box) complexes during early bovine embryogenesis. We inhibited it using MLN4924, an inhibitor of SCF complex ligases controlled by neddylation. Oocytes maturated in MLN4924 could be fertilized, but we found no cumulus cells expansion and a high number of polyspermy after in vitro fertilization...
December 7, 2018: Biology of Reproduction
Yun-Cheol Chae, Ji-Young Kim, Jin Woo Park, Kee-Beom Kim, Hyein Oh, Kyung-Hwa Lee, Sang-Beom Seo
Posttranslational modifications of the Forkhead family transcription factor, FOXO1, have been known to have important regulatory implications in its diverse activities. Several types of modifications of FOXO1, including acetylation, phosphorylation, and ubiquitination, have been reported. However, lysine methylation of FOXO1 has not yet been identified. Here, we reported that FOXO1 is methylated by G9a at K273 residue in vitro and in vivo. Methylation of FOXO1 by G9a increased interaction between FOXO1 and a specific E3 ligase, SKP2, and decreased FOXO1 protein stability...
December 7, 2018: Nucleic Acids Research
Xiongwei Yu, Wenjun Han, Changli Wang, Daming Sui, Jinjun Bian, Lulong Bo, Xiaoming Deng
Hemin, an inducer of heme oxygenase-1 (HO-1), can enhance the activation of HO-1. HO-1 exhibits a variety of activities, such as anti-inflammatory, antioxidative, and antiapoptotic functions. The objective of this study was to investigate the effects of hemin on sepsis-induced skeletal muscle wasting and to explore the mechanisms by which hemin exerts its effects. Cecal ligation and perforation (CLP) was performed to create a sepsis mouse model. Mice were randomly divided into four groups: control, CLP, CLP plus group, and CLP-hemin-ZnPP (a HO-1 inhibitor)...
2018: Oxidative Medicine and Cellular Longevity
Boya Liu, Jingjie Yi, Xin Yang, Lu Liu, Xinlin Lou, Zeyuan Zhang, Hao Qi, Zhe Wang, Junhua Zou, Wei-Guo Zhu, Wei Gu, Jianyuan Luo
MDM2 (Murine double minute 2) acts as a key repressor for p53-mediated tumor-suppressor functions, which includes cellular senescence. We found that MDM2 can promote cellular senescence by modulating WRN stability. Werner syndrome (WS), caused by mutations of the WRN gene, is an autosomal recessive disease, which is characterized by premature aging. Loss of WRN function induces cellular senescence in human cancer cells. Here, we found that MDM2 acts as an E3 ligase for WRN protein. MDM2 interacts with WRN both in vivo and in vitro...
December 7, 2018: Oncogene
Juliana Ferreira de Oliveira, Paula Favoretti Vital do Prado, Silvia Souza da Costa, Mauricio Luis Sforça, Camila Canateli, Americo Tavares Ranzani, Mariana Maschietto, Paulo Sergio Lopes de Oliveira, Paulo A Otto, Rachel E Klevit, Ana Cristina Victorino Krepischi, Carla Rosenberg, Kleber Gomes Franchini
Ubiquitin-conjugating enzymes (E2) enable protein ubiquitination by conjugating ubiquitin to their catalytic cysteine for subsequent transfer to a target lysine side chain. Deprotonation of the incoming lysine enables its nucleophilicity, but determinants of lysine activation remain poorly understood. We report a novel pathogenic mutation in the E2 UBE2A, identified in two brothers with mild intellectual disability. The pathogenic Q93E mutation yields UBE2A with impaired aminolysis activity but no loss of the ability to be conjugated with ubiquitin...
January 2019: Nature Chemical Biology
Julian A Poush, Nicolas A Blouin, Kristin R Di Bona, Vladimir Lažetić, David S Fay
RING-between-RING (RBR) E3 ubiquitin ligases are implicated in various developmental processes, and mutations in genes encoding RBR proteins HHARI/ARIH1 and Parkin are associated with human diseases. Here we show by phylogenetic analysis that the ARI1 family has undergone a dramatic expansion within the Caenorhabditis clade in recent history, a characteristic shared by some genes involved in germline development. We then examined the effects of deleting all ARI1 family members in the nematode Caenorhabditis elegans, which to our knowledge represents the first complete knockout of ARI1 function in a metazoan...
December 10, 2018: Scientific Reports
Yo-Chuen Lin, Yating Wang, Rosaline Hsu, Sumanprava Giri, Susan Wopat, Mariam K Arif, Arindam Chakraborty, Kannanganattu V Prasanth, Supriya G Prasanth
RING finger and WD repeat domain-containing protein 3 (RFWD3) is an E3 ligase known to facilitate homologous recombination by removing replication protein A (RPA) and RAD51 from DNA damage sites. Further, RPA-mediated recruitment of RFWD3 to stalled replication forks is essential for interstrand cross-link repair. Here, we report that in unperturbed human cells, RFWD3 localizes at replication forks and associates with proliferating cell nuclear antigen (PCNA) via its PCNA-interacting protein (PIP) motif. PCNA association is critical for the stability of RFWD3 and for DNA replication...
December 10, 2018: Proceedings of the National Academy of Sciences of the United States of America
Xinyi Fu, Vladyslava Sokolova, Kristofor J Webb, William Old, Soyeon Park
In the proteasome holoenzyme, the hexameric ATPases (Rpt1-Rpt6) enable degradation of ubiquitinated proteins by unfolding and translocating them into the proteolytic core particle. During early-stage proteasome assembly, individual Rpt proteins assemble into the hexameric "Rpt ring" through binding to their cognate chaperones: Nas2, Hsm3, Nas6, and Rpn14. Here, we show that Rpt ring assembly employs a specific ubiquitination-mediated control. An E3 ligase, Not4, selectively ubiquitinates Rpt5 during Rpt ring assembly...
December 10, 2018: Proceedings of the National Academy of Sciences of the United States of America
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