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https://read.qxmd.com/read/30771432/identification-and-characterization-of-small-molecule-inhibitors-of-the-ubiquitin-ligases-siah1-2-in-melanoma-and-prostate-cancer-cells
#1
Yongmei Feng, E Hampton Sessions, Fan Zhang, Fuqiang Ban, Veronica Placencio-Hickok, Chen-Ting Ma, Fu-Yue Zeng, Ian Pass, David B Terry, Gregory Cadwell, Laurie A Bankston, Robert C Liddington, Thomas D Y Chung, Anthony B Pinkerton, Eduard Sergienko, Martin Gleave, Neil Bhowmick, Michael R Jackson, Artem Cherkasov, Ze'ev A Ronai
Inhibition of ubiquitin ligases with small molecule remains a very challenging task, given the lack of catalytic activity of the target and the requirement of disruption of its interactions with other proteins. Siah1/2, which are E3 ubiquitin ligases, are implicated in melanoma and prostate cancer and represent high-value drug targets. We utilized three independent screening approaches in our efforts to identify small-molecule Siah1/2 inhibitors: Affinity Selection-Mass Spectrometry, a protein thermal shift-based assay and an in silico based screen...
February 13, 2019: Cancer Letters
https://read.qxmd.com/read/30760603/anaphase-promoting-complex-cyclosome-regulates-rddm-activity-by-degrading-dms3-in-arabidopsis
#2
Songxiao Zhong, Yifeng Xu, Chaoyi Yu, Xiaotuo Zhang, Lei Li, Haoran Ge, Guodong Ren, Yingxiang Wang, Jinbiao Ma, Yun Zheng, Binglian Zheng
During RNA-directed DNA methylation (RdDM), the DDR complex, composed of DRD1, DMS3, and RDM1, is responsible for recruiting DNA polymerase V (Pol V) to silence transposable elements (TEs) in plants. However, how the DDR complex is regulated remains unexplored. Here, we show that the anaphase-promoting complex/cyclosome (APC/C) regulates the assembly of the DDR complex by targeting DMS3 for degradation. We found that a substantial set of RdDM loci was commonly de-repressed in apc/c and pol v mutants, and that the defects in RdDM activity resulted from up-regulated DMS3 protein levels, which finally caused reduced Pol V recruitment...
February 13, 2019: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/30760601/role-of-uchl1-in-axonal-injury-and-functional-recovery-after-cerebral-ischemia
#3
Hao Liu, Nadya Povysheva, Marie E Rose, Zhiping Mi, Joseph S Banton, Wenjin Li, Fenghua Chen, Daniel P Reay, Germán Barrionuevo, Feng Zhang, Steven H Graham
Ubiquitin C-terminal hydrolase L1 (UCHL1) is a unique brain-specific deubiquitinating enzyme. Mutations in and aberrant function of UCHL1 have been linked to many neurological disorders. UCHL1 activity protects neurons from hypoxic injury, and binding of stroke-induced reactive lipid species to the cysteine 152 (C152) of UCHL1 unfolds the protein and disrupts its function. To investigate the role of UCHL1 and its adduction by reactive lipids in inhibiting repair and recovery of function following ischemic injury, a knock-in (KI) mouse expressing the UCHL1 C152A mutation was generated...
February 13, 2019: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/30759391/march8-ubiquitinates-the-hepatitis-c-virus-nonstructural-2-protein-and-mediates-viral-envelopment
#4
Sathish Kumar, Rina Barouch-Bentov, Fei Xiao, Stanford Schor, Szuyuan Pu, Elise Biquand, Albert Lu, Brett D Lindenbach, Yves Jacob, Caroline Demeret, Shirit Einav
The mechanisms that regulate envelopment of HCV and other viruses that bud intracellularly and/or lack late-domain motifs are largely unknown. We reported that K63 polyubiquitination of the HCV nonstructural (NS) 2 protein mediates HRS (ESCRT-0 component) binding and envelopment. Nevertheless, the ubiquitin signaling that governs NS2 ubiquitination remained unknown. Here, we map the NS2 interactome with the ubiquitin proteasome system (UPS) via mammalian cell-based screens. NS2 interacts with E3 ligases, deubiquitinases, and ligase regulators, some of which are candidate proviral or antiviral factors...
February 12, 2019: Cell Reports
https://read.qxmd.com/read/30758996/the-hect-ubiquitin-e3-ligase-smurf2-degrades-%C3%AE-opioid-receptor-1-in-the-ubiquitin-proteasome-system-in-lung-epithelial-cells
#5
Su Dong, Jia Liu, Lian Li, Heather Wang, Haichun Ma, Yutong Zhao, Jing Zhao
Opioids are widely used for relieving clinical acute or chronic pain. The biological effects of opioids are through activating the μ-opioid receptors 1 (MOR1). Most studies have focused on the consequences of agonist-induced MOR1 phosphorylation, ubiquitination, and internalization. Agonist-mediated MOR1 degradation, which is crucial for receptor stability and responsiveness, has not been well studied. The HECT ubiquitin E3 ligase Smurf2 has been shown to regulate MOR1 ubiquitination and internalization, however, its role in MOR1 degradation has not been studied...
February 13, 2019: American Journal of Physiology. Cell Physiology
https://read.qxmd.com/read/30758987/toll-like-receptor-3-controls-qt-interval-on-the-electrocardiogram-by-targeting-the-degradation-of-kv4-2-4-3-channels-in-the-endoplasmic-reticulum
#6
Xueting Gao, Siyun Gao, Yi Guan, Lin Huang, Jiale Huang, Li Lin, Yuan Liu, Hong Zhao, Bijun Huang, Tianyou Yuan, Yi Liu, Dandan Liang, Yangyang Zhang, Xiue Ma, Li Li, Jun Li, Daizhan Zhou, Dan Shi, Liang Xu, Yi-Han Chen
TLRs have been proven to be essential mediators for the early innate immune response. Overactivation of TLR-mediated immune signaling promotes deterioration of cardiovascular diseases; however, the role of TLRs in the heart under physiologic conditions remains neglected. Here, we show that Tlr3 deficiency induced the endoplasmic reticulum (ER) retention of Kv4.2/4.3 proteins and consequent degradation via the ubiquitin-proteasome pathway. Knockout of Tlr3 resulted in a prolonged QT interval (the space between the start of the Q wave and the end of the T wave) in mice with no significant signs of inflammation and tissue abnormality in cardiac muscles...
February 13, 2019: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://read.qxmd.com/read/30746447/-porphyromonas-gingivalis-in-alzheimer-s-disease-brains-evidence-for-disease-causation-and-treatment-with-small-molecule-inhibitors
#7
Stephen S Dominy, Casey Lynch, Florian Ermini, Malgorzata Benedyk, Agata Marczyk, Andrei Konradi, Mai Nguyen, Ursula Haditsch, Debasish Raha, Christina Griffin, Leslie J Holsinger, Shirin Arastu-Kapur, Samer Kaba, Alexander Lee, Mark I Ryder, Barbara Potempa, Piotr Mydel, Annelie Hellvard, Karina Adamowicz, Hatice Hasturk, Glenn D Walker, Eric C Reynolds, Richard L M Faull, Maurice A Curtis, Mike Dragunow, Jan Potempa
Porphyromonas gingivalis , the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer's disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer's patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1-42 , a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function...
January 2019: Science Advances
https://read.qxmd.com/read/30735793/microrna-related-markers-associated-with-corpus-luteum-tropism-in-buffalo-bubalus-bubalis
#8
A Jerome, J Bhati, D C Mishra, K K Chaturvedi, A R Rao, A Rai, P Sikka, I Singh
The study was undertaken to decipher the microRNA (miRNA) related markers associated with corpus luteum (CL) tropism in buffalo. The data obtained from deep sequencing of CL tissue from different physiological stages was mined in silico for the identification of miRNA-related markers (SSR & SNP). From the present study, 5 annotated and 176 unannotated miRNA were deduced while comparing with Bos taurus genome. In addition, 4 SSRs and 9 SNPs were deduced from the miRNA sequences. These SSRs were on the genes viz...
February 5, 2019: Genomics
https://read.qxmd.com/read/30732588/trail-signals-through-the-ubiquitin-ligase-mid1-to-promote-pulmonary-fibrosis
#9
Adam M Collison, Junyao Li, Ana Pereira de Siqueira, Xuejiao Lv, Hamish D Toop, Jonathan C Morris, Malcolm R Starkey, Philip M Hansbro, Jie Zhang, Joerg Mattes
BACKGROUND: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has previously been demonstrated to play a pro-inflammatory role in allergic airways disease and COPD through the upregulation of the E3 ubiquitin ligase MID1 and the subsequent deactivation of protein phosphatase 2A (PP2A). METHODS: Biopsies were taken from eight IPF patients presenting to the Second Affiliated Hospital of Jilin University, China between January 2013 and February 2014 with control samples obtained from resected lung cancers...
February 7, 2019: BMC Pulmonary Medicine
https://read.qxmd.com/read/30709918/tissue-type-plasminogen-activator-regulates-p35-mediated-cdk5-activation-in-the-postsynaptic-terminal
#10
Ariel Diaz, Valerie Jeanneret, Paola Merino, Patrick McCann, Manuel Yepes
Neuronal depolarization induces the synaptic release of tissue-type plasminogen activator (tPA). Cyclin dependent kinase-5 (Cdk5) is a member of the family of cyclin-dependent kinases that regulates cell migration and synaptic function in postmitotic neurons. Cdk5 is activated by its binding to p35, a membrane-anchored protein that is rapidly degraded by the proteasome. Here we show that tPA prevents the degradation of p35 in the synapse by a plasminogen-dependent mechanism that requires open synaptic N-Methyl-D-Aspartate (NMDA) receptors...
February 1, 2019: Journal of Cell Science
https://read.qxmd.com/read/30705969/therapeutic-advantages-of-dual-targeting-of-ppar-%C3%AE-and-ppar-%C3%AE-in-an-experimental-model-of-sporadic-alzheimer-s-disease
#11
D Reich, G Gallucci, M Tong, S M de la Monte
Background: Alzheimer's disease (AD) is associated with progressive impairments in brain responsiveness to insulin and insulin-like growth factor (IGF). Although deficiencies in brain insulin and IGF could be ameliorated with trophic factors such as insulin, impairments in receptor expression, binding, and tyrosine kinase activation require alternative strategies. Peroxisome proliferator-activated receptor (PPAR) agonists target genes downstream of insulin/IGF stimulation. Furthermore, their anti-oxidant and anti-inflammatory effects address other pathologies contributing to neurodegeneration...
May 2018: Journal of Parkinson's Disease and Alzheimer's Disease
https://read.qxmd.com/read/30699121/early-girl-is-a-novel-component-of-the-fat-signaling-pathway
#12
Jyoti R Misra, Kenneth D Irvine
The Drosophila protocadherins Dachsous and Fat regulate growth and tissue polarity by modulating the levels, membrane localization and polarity of the atypical myosin Dachs. Localization to the apical junctional membrane is critical for Dachs function, and the adapter protein Vamana/Dlish and palmitoyl transferase Approximated are required for Dachs membrane localization. However, how Dachs levels are regulated is poorly understood. Here we identify the early girl gene as playing an essential role in Fat signaling by limiting the levels of Dachs protein...
January 30, 2019: PLoS Genetics
https://read.qxmd.com/read/30698894/vitamin-d-protects-against-particles-caused-lung-injury-through-induction-of-autophagy-in-an-nrf2-dependent-manner
#13
Shasha Tao, Hong Zhang, Lian Xue, Xiaoyan Jiang, Hongyan Wang, Bingyan Li, Hailin Tian, Zengli Zhang
Fine particulate matter is a well-known air pollutant threatening public health. Studies have confirmed long-term exposure to the particles could decrease the pulmonary function, induce asthma exacerbation, and chronic obstructive pulmonary disease, as well as increase the incidence and mortality of lung cancer. A clinical study has explored that the prevalence and risks of vitamin D (VD) deficiency in various chronic disease and toxins induced tissue damage. Our current study aimed to explore the mechanism and further therapeutic potential of VD administration to ameliorate fine particles exposure induced pulmonary damage in vivo and in vitro...
January 30, 2019: Environmental Toxicology
https://read.qxmd.com/read/30695054/vgsc-interacting-proteins-are-genetically-associated-with-pyrethroid-resistance-in-aedes-aegypti
#14
Corey L Campbell, Karla Saavedra-Rodriguez, Tristan D Kubik, Audrey Lenhart, Saul Lozano-Fuentes, William C Black
Association mapping of factors that condition pyrethroid resistance in Aedes aegypti has consistently identified genes in multiple functional groups. Toward better understanding of the mechanisms involved, we examined high throughput sequencing data (HTS) from two Aedes aegypti aegypti collections from Merida, Yucatan, Mexico treated with either permethrin or deltamethrin. Exome capture enrichment for coding regions and the AaegL5 annotation were used to identify genes statistically associated with resistance...
2019: PloS One
https://read.qxmd.com/read/30694439/-1-h-15-n-and-13-c-backbone-assignment-of-apo-tdp-43-rna-recognition-motifs
#15
David D Scott, Liberty Francois-Moutal, Vlad K Kumirov, May Khanna
TAR DNA-binding protein 43 (TDP-43) is a ubiquitously expressed nuclear protein that influences diverse cellular processes by regulating alternative splicing of RNA and microRNA biogenesis. It is also a pathological protein found in sporadic ALS and in the most common subtype of frontotemporal lobar degeneration with ubiquitinated inclusions (FLTD-U). TDP-43 has two tandem RNA-binding domains, RRM1 and RRM2. The NMR structure of TDP-43 was solved in the presence of UG-rich RNA sequences bound to the RRM1 and RRM2 domains...
January 29, 2019: Biomolecular NMR Assignments
https://read.qxmd.com/read/30692207/a-znrf3-dependent-wnt-%C3%AE-catenin-signaling-gradient-is-required-for-adrenal-homeostasis
#16
Kaitlin J Basham, Stéphanie Rodriguez, Adina F Turcu, Antonio M Lerario, Catriona Y Logan, Madeline R Rysztak, Celso E Gomez-Sanchez, David T Breault, Bon-Kyoung Koo, Hans Clevers, Roeland Nusse, Pierre Val, Gary D Hammer
Spatiotemporal control of Wnt signaling is essential for the development and homeostasis of many tissues. The transmembrane E3 ubiquitin ligases ZNRF3 (zinc and ring finger 3) and RNF43 (ring finger protein 43) antagonize Wnt signaling by promoting degradation of frizzled receptors. ZNRF3 and RNF43 are frequently inactivated in human cancer, but the molecular and therapeutic implications remain unclear. Here, we demonstrate that adrenocortical-specific loss of ZNRF3, but not RNF43, results in adrenal hyperplasia that depends on Porcupine-mediated Wnt ligand secretion...
January 28, 2019: Genes & Development
https://read.qxmd.com/read/30692204/a-conserved-caf40-binding-motif-in-metazoan-not4-mediates-association-with-the-ccr4-not-complex
#17
Csilla Keskeny, Tobias Raisch, Annamaria Sgromo, Cátia Igreja, Dipankar Bhandari, Oliver Weichenrieder, Elisa Izaurralde
The multisubunit CCR4-NOT mRNA deadenylase complex plays important roles in the posttranscriptional regulation of gene expression. The NOT4 E3 ubiquitin ligase is a stable component of the CCR4-NOT complex in yeast but does not copurify with the human or Drosophila melanogaster complex. Here we show that the C-terminal regions of human and D. melanogaster NOT4 contain a conserved sequence motif that directly binds the CAF40 subunit of the CCR4-NOT complex (CAF40-binding motif [CBM]). In addition, nonconserved sequences flanking the CBM also contact other subunits of the complex...
January 28, 2019: Genes & Development
https://read.qxmd.com/read/30674673/a-bipartite-boundary-element-restricts-ube3a-imprinting-to-mature-neurons
#18
Jack S Hsiao, Noelle D Germain, Andrea Wilderman, Christopher Stoddard, Luke A Wojenski, Geno J Villafano, Leighton Core, Justin Cotney, Stormy J Chamberlain
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of UBE3A , a gene encoding an E3 ubiquitin ligase. UBE3A is only expressed from the maternally inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of UBE3A is restricted to neurons by expression of UBE3A antisense transcript ( UBE3A-ATS ) from the paternally inherited allele, which silences the paternal allele of UBE3A in cis However, the mechanism restricting UBE3A-ATS expression and UBE3A imprinting to neurons is not understood...
January 23, 2019: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/30661797/a-flower-specific-phospholipase-d-is-a-stigmatic-compatibility-factor-targeted-by-the-self-incompatibility-response-in-brassica-napus
#19
Sabine Scandola, Marcus A Samuel
Self-incompatibility (SI) is a genetic mechanism in hermaphroditic flowers that prevents inbreeding by rejection of self-pollen, while allowing cross- or genetically diverse pollen to germinate on the stigma to successfully fertilize the ovules. In Brassica, SI is initiated by the allele-specific recognition of pollen-encoded, secreted ligand (SCR/SP11) by the stigmatic receptor kinase S-locus receptor kinase (SRK), resulting in activation of SRK through phosphorylation [1-3]. Once activated, this phospho-relay converges on intracellular compatibility factors, which are immediately targeted for degradation by the E3 ligase, ARC1, resulting in the pollen rejection response [4, 5]...
January 9, 2019: Current Biology: CB
https://read.qxmd.com/read/30658107/f-box-protein-mediated-resistance-to-parp-inhibitor-therapy
#20
Aleksandra I Adamovich, Amanda Ewart Toland, Jeffrey D Parvin
PARP inhibitor (PARPi) therapy targets BRCA1/2 mutant tumor cells, but acquired resistance limits its effectiveness. In this issue of Molecular Cell, Marzio et al. (2019) identify a novel mechanism of resistance to PARPi through regulation of RAD51 protein stability via an SCF ubiquitin ligase dependent on EMI1.
January 17, 2019: Molecular Cell
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