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Manuel Ar Ferreira, Judith M Vonk, Hansjörg Baurecht, Ingo Marenholz, Chao Tian, Joshua D Hoffman, Quinta Helmer, Annika Tillander, Vilhelmina Ullemar, Yi Lu, Franz Rüschendorf, David A Hinds, Norbert Hübner, Stephan Weidinger, Patrik Ke Magnusson, Eric Jorgenson, Young-Ae Lee, Dorret I Boomsma, Robert Karlsson, Catarina Almqvist, Gerard H Koppelman, Lavinia Paternoster
BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities. OBJECTIVE: To identify novel risk loci shared between asthma, hay fever and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 individuals...
April 18, 2018: Journal of Allergy and Clinical Immunology
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 (CRL4VprBP ), 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
Hong Yan, Lei Bi, Yunshan Wang, Xia Zhang, Zhibo Hou, Qian Wang, Antoine M Snijders, Jian-Hua Mao
Many DDB1-CUL4 associated factors (DCAFs) have been identified and serve as substrate receptors. Although the oncogenic role of CUL4A has been well established, specific DCAFs involved in cancer development remain largely unknown. Here we infer the potential impact of 19 well-defined DCAFs in human lung adenocarcinomas (LuADCs) using integrative omics analyses, and discover that mRNA levels of DTL, DCAF4, 12 and 13 are consistently elevated whereas VBRBP is reduced in LuADCs compared to normal lung tissues...
March 23, 2017: Scientific Reports
Anne Sadewasser, Katharina Paki, Katrin Eichelbaum, Boris Bogdanow, Sandra Saenger, Matthias Budt, Markus Lesch, Klaus-Peter Hinz, Andreas Herrmann, Thomas F Meyer, Alexander Karlas, Matthias Selbach, Thorsten Wolff
Influenza A virus (IAV) infections are a major cause for respiratory disease in humans, which affects all age groups and contributes substantially to global morbidity and mortality. IAV have a large natural host reservoir in avian species. However, many avian IAV strains lack adaptation to other hosts and hardly propagate in humans. While seasonal or pandemic IAV strains replicate efficiently in permissive human cells, many avian IAV cause abortive nonproductive infections in these hosts despite successful cell entry...
May 2017: Molecular & Cellular Proteomics: MCP
Delowar Hossain, Yalda Javadi Esfehani, Arindam Das, William Y Tsang
The centrosome plays a critical role in various cellular processes including cell division and cilia formation, and deregulation of centrosome homeostasis is a hallmark feature of many human diseases. Here, we show that centrosomal protein of 78 kDa (Cep78) localizes to mature centrioles and directly interacts with viral protein R binding protein (VprBP). Although VprBP is a component of two distinct E3 ubiquitin ligases, EDD-DYRK2-DDB1(Vpr)(BP) and CRL4(Vpr)(BP), Cep78 binds specifically to EDD-DYRK2-DDB1(Vpr)(BP) and inhibits its activity...
April 2017: EMBO Reports
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
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
Bizhan Romani, Nima Shaykh Baygloo, Mojtaba Hamidi-Fard, Mohammad Reza Aghasadeghi, Elham Allahbakhshi
Mechanisms underlying HIV-1 latency remain among the most crucial questions that need to be answered to adopt strategies for purging the latent viral reservoirs. Here we show that HIV-1 accessory protein Vpr induces depletion of class I HDACs, including HDAC1, 2, 3, and 8, to overcome latency in macrophages. We found that Vpr binds and depletes chromatin-associated class I HDACs through a VprBP-dependent mechanism, with HDAC3 as the most affected class I HDAC. De novo expression of Vpr in infected macrophages induced depletion of HDAC1 and 3 on the HIV-1 LTR that was associated with hyperacetylation of histones on the HIV-1 LTR...
February 5, 2016: Journal of Biological Chemistry
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
Victoria L Palmer, Razia Aziz-Seible, Michele D Kassmeier, Mary Rothermund, Greg A Perry, Patrick C Swanson
B cell development past the pro-B cell stage in mice requires the Cul4-Roc1-DDB1 E3 ubiquitin ligase substrate recognition subunit VprBP. Enforced Bcl2 expression overcomes defects in distal VH-DJH and secondary Vκ-Jκ rearrangement associated with VprBP insufficiency in B cells and substantially rescues maturation of marginal zone and Igλ(+) B cells, but not Igκ(+) B cells. In this background, expression of a site-directed Igκ L chain transgene increases Igκ(+) B cell frequency, suggesting VprBP does not regulate L chain expression from a productively rearranged Igk allele...
August 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Bizhan Romani, Nima Shaykh Baygloo, Mohammad Reza Aghasadeghi, Elham Allahbakhshi
Human immunodeficiency virus type 1 Vpr is an accessory protein that induces G2/M cell cycle arrest. It is well documented that interaction of Vpr with the Cul4-DDB1[VprBP] E3 ubiquitin ligase is essential for the induction of G2/M arrest. In this study, we show that HIV-1 Vpr indirectly binds MCM10, a eukaryotic DNA replication factor, in a Vpr-binding protein (VprBP) (VprBP)-dependent manner. Binding of Vpr to MCM10 enhanced ubiquitination and proteasomal degradation of MCM10. G2/M-defective mutants of Vpr were not able to deplete MCM10, and we show that Vpr-induced depletion of MCM10 is related to the ability of Vpr to induce G2/M arrest...
July 10, 2015: Journal of Biological Chemistry
Kazunari Yamashita, Mariko Ide, Kana T Furukawa, Atsushi Suzuki, Hisashi Hirano, Shigeo Ohno
Lethal giant larvae (Lgl) is an evolutionarily conserved tumor suppressor whose loss of function causes disrupted epithelial architecture with enhanced cell proliferation and defects in cell polarity. A role for Lgl in the establishment and maintenance of cell polarity via suppression of the PAR-aPKC polarity complex is established; however, the mechanism by which Lgl regulates cell proliferation is not fully understood. Here we show that depletion of Lgl1 and Lgl2 in MDCK epithelial cells results in overproliferation and overproduction of Lgl2 causes G1 arrest...
July 1, 2015: Molecular Biology of the Cell
(no author information available yet)
CRL4(VprBP)-mediated monoubiquitylation of TET enzymes promotes their chromatin binding activity.
February 2015: Cancer Discovery
Tadashi Nakagawa, Lei Lv, Makiko Nakagawa, Yanbao Yu, Chao Yu, Ana C D'Alessio, Keiko Nakayama, Heng-Yu Fan, Xian Chen, Yue Xiong
DNA methylation at the C-5 position of cytosine (5mC) regulates gene expression and plays pivotal roles in various biological processes. The TET dioxygenases catalyze iterative oxidation of 5mC, leading to eventual demethylation. Inactivation of TET enzymes causes multistage developmental defects, impaired cell reprogramming, and hematopoietic malignancies. However, little is known about how TET activity is regulated. Here we show that all three TET proteins bind to VprBP and are monoubiquitylated by the VprBP-DDB1-CUL4-ROC1 E3 ubiquitin ligase (CRL4(VprBP)) on a highly conserved lysine residue...
January 22, 2015: Molecular Cell
Burcu Biterge, Florian Richter, Gerhard Mittler, Robert Schneider
Histone modifications play crucial roles in modulating chromatin function and transcriptional activity. Due to their long half-life, histones can, in addition to post-translational modifications, also accumulate spontaneous chemical alterations, which can affect their functionality and require either protein repair or degradation. One of the major sources of such protein damage or ageing is the conversion of aspartate into isoaspartate residues that can then be methylated. Here, we characterize a novel histone modification, the methylation of histone H4 at aspartate 24 (H4D24me)...
2014: Scientific Reports
Dawei Zhou, Yan Wang, Kenzo Tokunaga, Fang Huang, Binlian Sun, Rongge Yang
The host anti-HIV-1 factor APOBEC3G (A3G) plays a potential role in restricting HIV-1 replication, although this antagonist can be encountered and disarmed by the Vif protein. In this paper, we report that another HIV-1 accessory protein, viral protein R (Vpr), can interact with A3G and intervene in its antiviral behavior. The interaction of Vpr and A3G was predicted by computer-based screen and confirmed by a co-immunoprecipitation (Co-IP) approach. We found that Vpr could reduce the virion encapsidation of A3G to enhance viral replication...
January 2, 2015: Virus Research
Ting Yuan, Weitong Yao, Fang Huang, Binlian Sun, Rongge Yang
TRIM11 has been reported to be able to restrict HIV-1 replication, but the detailed aspects of the interfering mechanisms remain unclear. In this study, we demonstrated that TRIM11 mainly suppressed the early steps of HIV-1 transduction, resulting in decreased reverse transcripts. Additionally, we found that TRIM11 could inhibit HIV-1 long terminal repeat (LTR) activity, which may be related to its inhibitory effects on NF-κB. Deletion mutant experiments showed that the RING domain of TRIM11 was indispensable in inhibiting the early steps of HIV-1 transduction but was dispensable in decreasing NF-κB and LTR activities...
2014: PloS One
Li Ma, Chan-Juan Shen, Éric A Cohen, Si-Dong Xiong, Jian-Hua Wang
Primary monocytes are refractory to HIV-1 infection and become permissive upon differentiation into monocyte-derived dendritic cells (MDDCs) or macrophages. Multiple mechanisms have been proposed to interpret HIV-1 restriction in monocytes. Human cellular miRNAs can modulate HIV-1 infection by targeting either conserved regions of the HIV-1 genome or host gene transcripts. We have recently reported that the translation of host protein pur-alpha is repressed by abundant cellular miRNAs to inhibit HIV-1 infection in monocytes...
2014: PloS One
Youjun Li, Zhiyi Wei, Junyi Zhang, Zhou Yang, Mingjie Zhang
The tumor suppressor gene Nf2 product, Merlin, plays vital roles in controlling proper development of organ sizes by specifically binding to a large number of target proteins localized both in cytoplasm and nuclei. The FERM domain of Merlin is chiefly responsible for its binding to target proteins, although the molecular basis governing these interactions are poorly understood due to lack of structural information. Here, we report the crystal structure of the Merlin FERM domain in complex with its binding domain derived from the E3 ubiquitin ligase substrate adaptor DCAF1 (also known as VPRBP)...
May 23, 2014: Journal of Biological Chemistry
Francine C A Gérard, Ruifeng Yang, Bizhan Romani, Alexis Poisson, Jean-Philippe Belzile, Nicole Rougeau, Éric A Cohen
HIV viral protein R (Vpr) induces a cell cycle arrest at the G2/M phase by activating the ATR DNA damage/replication stress signalling pathway through engagement of the DDB1-CUL4A-DCAF1 E3 ubiquitin ligase via a direct binding to the substrate specificity receptor DCAF1. Since no high resolution structures of the DDB1-DCAF1-Vpr substrate recognition module currently exist, we used a mutagenesis approach to better define motifs in DCAF1 that are crucial for Vpr and DDB1 binding. Herein, we show that the minimal domain of DCAF1 that retained the ability to bind Vpr and DDB1 was mapped to residues 1041 to 1393 (DCAF1 WD)...
2014: PloS One
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