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https://www.readbyqxmd.com/read/28803141/the-poly-proline-tail-of-sivmac-vpx-provides-gain-of-function-for-resistance-to-a-cryptic-proteasome-dependent-degradation-pathway
#1
Nannan Zhang, Haoran Guo, Jiaxin Yang, Guanchen Liu, Shuang Li, Siying Li, Dongyin Wang, Rui Li, Chang Shu, Hongmei Xu, Zhentong Wei, Honglan Huang, Songling Zhang, Pujun Gao, Shan Cen, Richard Markham, Yongsheng Wang, Xiao-Fang Yu, Wei Wei
The lentiviral accessory protein Vpx is critical for viral infection of myeloid cells and acts by hijacking CRL4(DCAF1) E3 ubiquitin ligase to induce the degradation of the host restriction factor SAMHD1. It has been observed that the sequences from HIV-2 and SIVsmm/SIVmac Vpx contain a poly-proline tail which is distinct from other SIV Vpx proteins. However, the role of this region in Vpx function is controversial. Herein, we found proteasome-dependent degradation of a Vpx mutant lacking the poly-proline tail in the nucleus in a CRL4(DCAF1) E3 ligase-independent fashion...
August 10, 2017: Virology
https://www.readbyqxmd.com/read/28623141/sirtuin-7-dependent-deacetylation-of-ddb1-regulates-the-expression-of-nuclear-receptor-tr4
#2
Md Fazlul Karim, Tatsuya Yoshizawa, Shihab U Sobuz, Yoshifumi Sato, Kazuya Yamagata
Sirtuin 7 (SIRT7) is an NAD(+)-dependent deacetylase/deacylase, but only a limited number of SIRT7 substrates have been identified. Recently, we found that Sirt7 knockout mice are resistant to high-fat diet-induced fatty liver, and that SIRT7 positively regulates the protein level of TR4, a nuclear receptor involved in lipid metabolism, by inhibiting the CUL4B/DDB1/DCAF1 E3 ubiquitin ligase complex. However, the mechanism by which SIRT7 inhibits the E3 ubiquitin ligase complex was not identified. Here, we demonstrate that SIRT7 binds directly to DDB1 and deacetylates DDB1 at Lys1121...
August 19, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28468780/combined-inhibition-of-nedd8-activating-enzyme-and-mtor-suppresses-nf2-loss-driven-tumorigenesis
#3
Jonathan Cooper, Qingwen Xu, Lu Zhou, Milica Pavlovic, Virginia Ojeda, Kamalika Moulick, Elisa de Stanchina, John T Poirier, Marjorie Zauderer, Charles M Rudin, Matthias A Karajannis, C Oliver Hanemann, Filippo G Giancotti
Inactivation of NF2/Merlin causes the autosomal-dominant cancer predisposition syndrome familial neurofibromatosis type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). To develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss drives tumorigenesis by activating the E3 ubiquitin ligase CRL4(DCAF1), thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, suppresses CRL4(DCAF1) and attenuates activation of YAP in NF2-mutant tumor cells...
May 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28424288/virion-associated-vpr-alleviates-a-postintegration-block-to-hiv-1-infection-of-dendritic-cells
#4
Caitlin M Miller, Hisashi Akiyama, Luis M Agosto, Ann Emery, Chelsea R Ettinger, Ronald I Swanstrom, Andrew J Henderson, Suryaram Gummuluru
Viral protein R (Vpr) is an HIV-1 accessory protein whose function remains poorly understood. In this report, we sought to determine the requirement of Vpr for facilitating HIV-1 infection of monocyte-derived dendritic cells (MDDCs), one of the first cell types to encounter virus in the peripheral mucosal tissues. In this report, we characterize a significant restriction of Vpr-deficient virus replication and spread in MDDCs alone and in cell-to-cell spread in MDDC-CD4(+) T cell cocultures. This restriction of HIV-1 replication in MDDCs was observed in a single round of virus replication and was rescued by the expression of Vpr in trans in the incoming virion...
July 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28416635/vprbp-dcaf1-regulates-the-degradation-and-nonproteolytic-activation-of-the-cell-cycle-transcription-factor-foxm1
#5
Xianxi Wang, Anthony Arceci, Kelly Bird, Christine A Mills, Rajarshi Choudhury, Jennifer L Kernan, Chunxiao Zhou, Victoria Bae-Jump, Albert Bowers, Michael J Emanuele
The oncogenic transcription factor FoxM1 plays a vital role in cell cycle progression, is activated in numerous human malignancies, and is linked to chromosome instability. We characterize here a cullin 4-based E3 ubiquitin ligase and its substrate receptor, VprBP/DCAF1 (CRL4(VprBP)), which we show regulate FoxM1 ubiquitylation and degradation. Paradoxically, we also found that the substrate receptor VprBP is a potent FoxM1 activator. VprBP depletion reduces expression of FoxM1 target genes and impairs mitotic entry, whereas ectopic VprBP expression strongly activates a FoxM1 transcriptional reporter...
July 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28202763/inhibition-of-vpx-mediated-samhd1-and-vpr-mediated-host-helicase-transcription-factor-degradation-by-selective-disruption-of-viral-crl4-dcaf1-e3-ubiquitin-ligase-assembly
#6
Hong Wang, Haoran Guo, Jiaming Su, Yajuan Rui, Wenwen Zheng, Wenying Gao, Wenyan Zhang, Zhaolong Li, Guanchen Liu, Richard B Markham, Wei Wei, Xiao-Fang Yu
The lentiviral accessory proteins Vpx and Vpr are known to utilize CRL4 (DCAF1) E3 ligase to induce the degradation of the host restriction factor SAMHD1 or host helicase transcription factor (HLTF), respectively. Selective disruption of viral CRL4 (DCAF1) E3 ligase could be a promising antiviral strategy. Recently, we have determined that posttranslational modification (neddylation) of Cullin-4 is required for the activation of Vpx-CRL4 (DCAF1) E3 ligase. However, the mechanism of Vpx/Vpr-CRL4 (DCAF1) E3 ligase assembly is still poorly understood...
May 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28068668/the-hippo-kinases-lats1-and-2-control-human-breast-cell-fate-via-crosstalk-with-er%C3%AE
#7
Adrian Britschgi, Stephan Duss, Sungeun Kim, Joana Pinto Couto, Heike Brinkhaus, Shany Koren, Duvini De Silva, Kirsten D Mertz, Daniela Kaup, Zsuzsanna Varga, Hans Voshol, Alexandra Vissieres, Cedric Leroy, Tim Roloff, Michael B Stadler, Christina H Scheel, Loren J Miraglia, Anthony P Orth, Ghislain M C Bonamy, Venkateshwar A Reddy, Mohamed Bentires-Alj
Cell fate perturbations underlie many human diseases, including breast cancer. Unfortunately, the mechanisms by which breast cell fate are regulated are largely unknown. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors. Breast cancer originates from this epithelium, but the molecular mechanisms that underlie breast epithelial hierarchy remain ill-defined. Here, we use a high-content confocal image-based short hairpin RNA screen to identify tumour suppressors that regulate breast cell fate in primary human breast epithelial cells...
January 26, 2017: Nature
https://www.readbyqxmd.com/read/27626385/acetylation-regulated-interaction-between-p53-and-set-reveals-a-widespread-regulatory-mode
#8
Donglai Wang, Ning Kon, Gorka Lasso, Le Jiang, Wenchuan Leng, Wei-Guo Zhu, Jun Qin, Barry Honig, Wei Gu
Although lysine acetylation is now recognized as a general protein modification for both histones and non-histone proteins, the mechanisms of acetylation-mediated actions are not completely understood. Acetylation of the C-terminal domain (CTD) of p53 (also known as TP53) was an early example of non-histone protein acetylation and its precise role remains unclear. Lysine acetylation often creates binding sites for bromodomain-containing 'reader' proteins. Here we use a proteomic screen to identify the oncoprotein SET as a major cellular factor whose binding with p53 is dependent on CTD acetylation status...
October 6, 2016: Nature
https://www.readbyqxmd.com/read/27571178/the-ddb1-dcaf1-vpr-ung2-crystal-structure-reveals-how-hiv-1-vpr-steers-human-ung2-toward-destruction
#9
Ying Wu, Xiaohong Zhou, Christopher O Barnes, Maria DeLucia, Aina E Cohen, Angela M Gronenborn, Jinwoo Ahn, Guillermo Calero
The HIV-1 accessory protein Vpr is required for efficient viral infection of macrophages and promotion of viral replication in T cells. Vpr's biological activities are closely linked to the interaction with human DCAF1, a cellular substrate receptor of the Cullin4-RING E3 ubiquitin ligase (CRL4) of the host ubiquitin-proteasome-mediated protein degradation pathway. The molecular details of how Vpr usurps the protein degradation pathway have not been delineated. Here we present the crystal structure of the DDB1-DCAF1-HIV-1-Vpr-uracil-DNA glycosylase (UNG2) complex...
October 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27460548/hiv-1-vpr-increases-hcv-replication-through-vprbp-in-cell-culture
#10
Yanling Yan, Fang Huang, Ting Yuan, Binlian Sun, Rongge Yang
Coinfection of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) occurs at a high frequency, in which HIV shows a promotion of HCV-derived liver diseases. However, the mechanism of how this occurs is not well understood. Our previous work has demonstrated that the HIV-1 accessory protein Vpr enhances HCV RNA replication in cell culture. Because Vpr performs most of its functions through host protein VprBP (DCAF1), the role of VprBP in the regulation of HCV by Vpr was investigated in this study...
September 2, 2016: Virus Research
https://www.readbyqxmd.com/read/27421984/-pathogenesis-and-molecular-pathology-of-vestibular-schwannoma
#11
M Brodhun, V Stahn, A Harder
Schwannomas are benign Schwann cell-derived tumors of the peripheral nerve sheath often involving the vestibular cranial nerve (vestibular schwannoma). Histologically, they consist of bipolar spindle cells and show a moderate cellularity. Typically, Antoni A regions with a storiform pattern and loose Antoni B regions are intermingled. Verocay bodies are the pathognomonic palisading structures. Malignant transformation is rare. Merlin (schwannomin), the protein product of NF2, is inactivated by mutations, loss of heterozygosity or methylation...
July 15, 2016: HNO
https://www.readbyqxmd.com/read/27354282/slx4-slx1-protein-independent-down-regulation-of-mus81-eme1-protein-by-hiv-1-viral-protein-r-vpr
#12
Xiaohong Zhou, Maria DeLucia, Jinwoo Ahn
Evolutionarily conserved structure-selective endonuclease MUS81 forms a complex with EME1 and further associates with another endonuclease SLX4-SLX1 to form a four-subunit complex of MUS81-EME1-SLX4-SLX1, coordinating distinctive biochemical activities of both endonucleases in DNA repair. Viral protein R (Vpr), a highly conserved accessory protein in primate lentiviruses, was previously reported to bind SLX4 to mediate down-regulation of MUS81. However, the detailed mechanism underlying MUS81 down-regulation is unclear...
August 12, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27335459/hiv-1-and-hiv-2-exhibit-divergent-interactions-with-hltf-and-ung2-dna-repair-proteins
#13
Kasia Hrecka, Caili Hao, Ming-Chieh Shun, Sarabpreet Kaur, Selene K Swanson, Laurence Florens, Michael P Washburn, Jacek Skowronski
HIV replication in nondividing host cells occurs in the presence of high concentrations of noncanonical dUTP, apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) cytidine deaminases, and SAMHD1 (a cell cycle-regulated dNTP triphosphohydrolase) dNTPase, which maintains low concentrations of canonical dNTPs in these cells. These conditions favor the introduction of marks of DNA damage into viral cDNA, and thereby prime it for processing by DNA repair enzymes. Accessory protein Vpr, found in all primate lentiviruses, and its HIV-2/simian immunodeficiency virus (SIV) SIVsm paralogue Vpx, hijack the CRL4(DCAF1) E3 ubiquitin ligase to alleviate some of these conditions, but the extent of their interactions with DNA repair proteins has not been thoroughly characterized...
July 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27114546/hiv-1-vpr-degrades-the-hltf-dna-translocase-in-t-cells-and-macrophages
#14
Hichem Lahouassa, Marie-Lise Blondot, Lise Chauveau, Ghina Chougui, Marina Morel, Marjorie Leduc, François Guillonneau, Bertha Cecilia Ramirez, Olivier Schwartz, Florence Margottin-Goguet
Viruses often interfere with the DNA damage response to better replicate in their hosts. The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) protein has been reported to modulate the activity of the DNA repair structure-specific endonuclease subunit (SLX4) complex and to promote cell cycle arrest. Vpr also interferes with the base-excision repair pathway by antagonizing the uracil DNA glycosylase (Ung2) enzyme. Using an unbiased quantitative proteomic screen, we report that Vpr down-regulates helicase-like transcription factor (HLTF), a DNA translocase involved in the repair of damaged replication forks...
May 10, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26965998/jak-stat3-pathway-triggers-dicer1-for-proteasomal-degradation-by-ubiquitin-ligase-complex-of-cul4a-dcaf1-to-promote-colon-cancer-development
#15
Weiguo Ren, Shourong Shen, Zhenqiang Sun, Peng Shu, Xiaohua Shen, Chibin Bu, Feiyan Ai, Xuemei Zhang, Anliu Tang, Li Tian, Guiyuan Li, Xiayu Li, Jian Ma
Chronic intestinal inflammation is closely associated with colon cancer development and STAT3 seems to take center stage in bridging chronic inflammation to colon cancer progress. Here, we discovered that DICER1 was significantly downregulated in response to IL-6 or LPS stimulation and identified a novel mechanism for DICER1 downregulation via proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) in colon cancer cells. Meanwhile, PI3K-AKT signaling pathway phosphorylated DICER1 and contributed to its proteasomal degradation...
June 1, 2016: Cancer Letters
https://www.readbyqxmd.com/read/26779819/hd-domain-of-samhd1-influences-vpx-induced-degradation-at-a-post-interaction-step
#16
Jian Kang, Jingwei Hou, Ke Zhao, Xiao-Fang Yu, Juan Du
Primate SAMHD1 proteins are potent inhibitors of viruses, including retroviruses such as HIV-1, HIV-2, and SIV. Vpx, a distinctive viral protein expressed by HIV-2 and some SIVs, induces SAMHD1 degradation by forming a Vpx-DCAF1-based ubiquitin ligase complex. Either the N- or the C-terminus of SAMHD1 is critical for Vpx-induced degradation, depending on the types of SAMHD1 and Vpx proteins. However, it was not fully understood whether other regions of SAMHD1 also contribute to its depletion by Vpx. In the present study, we report that SAMHD1 from chicken (SAMHD1GG) was not degraded by SIVmac Vpx, in contrast with results for human SAMHD1 (SAMHD1HS)...
February 12, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26549023/the-scaffold-protein-ksr1-a-novel-therapeutic-target-for-the-treatment-of-merlin-deficient-tumors
#17
L Zhou, J Lyons-Rimmer, S Ammoun, J Müller, E Lasonder, V Sharma, E Ercolano, D Hilton, I Taiwo, M Barczyk, C O Hanemann
Merlin has broad tumor-suppressor functions as its mutations have been identified in multiple benign tumors and malignant cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas Merlin loss is causative. In neurofibromatosis type 2, a dominantly inherited tumor disease because of the loss of Merlin, patients suffer from multiple nervous system tumors and die on average around age 40. Chemotherapy is not effective and tumor localization and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable...
June 30, 2016: Oncogene
https://www.readbyqxmd.com/read/26281983/crl4-dcaf1-ubiquitin-e3-ligase-directs-protein-phosphatase-2a-degradation-to-control-oocyte-meiotic-maturation
#18
Chao Yu, Shu-Yan Ji, Qian-Qian Sha, Qing-Yuan Sun, Heng-Yu Fan
Oocyte meiosis is a specialized cell cycle that gives rise to fertilizable haploid gametes and is precisely controlled in various dimensions. We recently found that E3 ubiquitin ligase CRL4 is required for female fertility by regulating DNA hydroxymethylation to maintain oocyte survival and to promote zygotic genome reprogramming. However, not all phenotypes of CRL4-deleted oocytes could be explained by this mechanism. Here we show that CRL4 controls oocyte meiotic maturation by proteasomal degradation of protein phosphatase 2A scaffold subunit, PP2A-A...
August 18, 2015: Nature Communications
https://www.readbyqxmd.com/read/26186441/vpr-promotes-macrophage-dependent-hiv-1-infection-of-cd4-t-lymphocytes
#19
David R Collins, Jay Lubow, Zana Lukic, Michael Mashiba, Kathleen L Collins
Vpr is a conserved primate lentiviral protein that promotes infection of T lymphocytes in vivo by an unknown mechanism. Here we demonstrate that Vpr and its cellular co-factor, DCAF1, are necessary for efficient cell-to-cell spread of HIV-1 from macrophages to CD4+ T lymphocytes when there is inadequate cell-free virus to support direct T lymphocyte infection. Remarkably, Vpr functioned to counteract a macrophage-specific intrinsic antiviral pathway that targeted Env-containing virions to LAMP1+ lysosomal compartments...
July 2015: PLoS Pathogens
https://www.readbyqxmd.com/read/26149774/jmjd2c-increases-myod-transcriptional-activity-through-inhibiting-g9a-dependent-myod-degradation
#20
Eun-Shil Jung, Ye-Ji Sim, Hoe-Su Jeong, Su-Jin Kim, Ye-Jin Yun, Joo-Hoon Song, Su-Hee Jeon, Chungyoul Choe, Kyung-Tae Park, Chang-Hoon Kim, Kye-Seong Kim
Skeletal muscle cell differentiation requires a family of proteins called myogenic regulatory factors (MRFs) to which MyoD belongs. The activity of MyoD is under epigenetic regulation, however, the molecular mechanism by which histone KMTs and KDMs regulate MyoD transcriptional activity through methylation remains to be determined. Here we provide evidence for a unique regulatory mechanism of MyoD transcriptional activity through demethylation by Jmjd2C demethylase whose level increases during muscle differentiation...
August 2015: Biochimica et Biophysica Acta
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