Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration During a Critical
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KCTD13 Is a Major Driver of Mirrored Neuroanatomical Phenotypes Associated with the 16P11.2 CNV
KCTD13 is a Major Driver of Mirrored Neuroanatomical Phenotypes Associated with the 16p11.2 CNV The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters. Citation Golzio, Christelle, Jason Willer, Michael E. Talkowski, Edwin C. Oh, Yu Taniguchi, Sébastien Jacquemont, Alexandre Reymond, et al. 2012. KCTD13 is a major driver of mirrored neuroanatomical phenotypes associated with the 16p11.2 CNV. Nature 485(7398): 363-367. Published Version doi:10.1038/nature11091 Accessed February 19, 2015 11:53:26 AM EST Citable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:10579139 Terms of Use This article was downloaded from Harvard University's DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA (Article begins on next page) NIH Public Access Author Manuscript Nature. Author manuscript; available in PMC 2012 November 16. Published in final edited form as: Nature. ; 485(7398): 363–367. doi:10.1038/nature11091. KCTD13 is a major driver of mirrored neuroanatomical phenotypes associated with the 16p11.2 CNV $watermark-text $watermark-text $watermark-text Christelle Golzio1, Jason Willer1, Michael E Talkowski2,3, Edwin C Oh1, Yu Taniguchi5, Sébastien Jacquemont4, Alexandre Reymond6, Mei Sun2, Akira Sawa5, James F Gusella2,3, Atsushi Kamiya5, Jacques S Beckmann4,7, and Nicholas Katsanis1,8 1Center for Human Disease Modeling and Dept of Cell biology, -
The Human Dcn1-Like Protein DCNL3 Promotes Cul3 Neddylation at Membranes
The human Dcn1-like protein DCNL3 promotes Cul3 neddylation at membranes Nathalie Meyer-Schallera, Yang-Chieh Choub,c, Izabela Sumaraa, Dale D. O. Martind, Thimo Kurza, Nadja Kathedera, Kay Hofmanne, Luc G. Berthiaumed, Frank Sicherib,c, and Matthias Petera,1 aInstitute of Biochemistry, Eidgeno¨ssiche Technische Hochschule, 8093 Zurich, Switzerland; bCenter for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, ON, Canada M5G 1X5; cDepartment of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8; dDepartment of Cell Biology, University of Alberta, Edmonton, AB, Canada T6G 2H7; and eBioinformatics Group, Miltenyi Biotec, 51429 Bergisch-Gladbach, Germany Edited by Michael Rape, University of California, Berkeley, CA, and accepted by the Editorial Board June 9, 2009 (received for review December 9, 2008) Cullin (Cul)-based E3 ubiquitin ligases are activated through the enzyme and promotes Nedd8 conjugation through formation of attachment of Nedd8 to the Cul protein. In yeast, Dcn1 (defective this complex (14, 15). Human cells harbor 5 Dcn1-like proteins in Cul neddylation 1 protein) functions as a scaffold-like Nedd8 termed DCNL1–DCNL5 (also named DCUN1D 1–5 for defec- E3-ligase by interacting with its Cul substrates and the Nedd8 E2 tive in Cul neddylation 1 domain-containing protein 1–5) (Fig. Ubc12. Human cells express 5 Dcn1-like (DCNL) proteins each S1). These DCNLs have distinct amino-terminal domains, but containing a C-terminal potentiating neddylation domain but dis- share a conserved C-terminal potentiating neddylation (PONY) tinct amino-terminal extensions. Although the UBA-containing domain, which in yeast Dcn1 is necessary and sufficient for Cul DCNL1 and DCNL2 are likely functional homologues of yeast Dcn1, neddylation in vivo and in vitro (14). -
Supp Material.Pdf
Supplementary Information Estrogen-mediated Epigenetic Repression of Large Chromosomal Regions through DNA Looping Pei-Yin Hsu, Hang-Kai Hsu, Gregory A. C. Singer, Pearlly S. Yan, Benjamin A. T. Rodriguez, Joseph C. Liu, Yu-I Weng, Daniel E. Deatherage, Zhong Chen, Julia S. Pereira, Ricardo Lopez, Jose Russo, Qianben Wang, Coral A. Lamartiniere, Kenneth P. Nephew, and Tim H.-M. Huang S1 Method Immunofluorescence staining Approximately 2,000 mammosphere-derived epithelial cells (MDECs) cells seeded collagen I-coated coverslips were fixed with methanol/acetone for 10 min. After blocking with 2.5% bovine serum albumin (Sigma) for 1 hr, these cells were incubated with anti-ESR1 antibody (Santa Cruz) overnight at 4˚C. The corresponding secondary FITC-conjugated antibody was applied followed by DAPI staining (Molecular Probes) for the nuclei. Photographs were captured by Zeiss fluorescence microscopy (Zeiss). The percentages of ESR1 subcellular localization were calculated in ten different optical fields (~10 cells per field) by two independent researchers. References Carroll, J.S., Meyer, C.A., Song, J., Li, W., Geistlinger, T.R., Eeckhoute, J., Brodsky, A.S., Keeton, E.K., Fertuck, K.C., Hall, G.F., et al. 2006. Genome-wide analysis of estrogen receptor binding sites. Nat. Genet. 38: 1289-1297. Neve, R.M., Chin, K., Fridlyand, J., Yeh, J., Baehner, F.L., Fevr, T., Clark, L., Bayani, N., Coppe, J.P., Tong, F., et al. 2006. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10: 515-527. S2 Hsu et al. Supplementary Information A Figure S1. Integrative mapping of large genomic regions subjected to ERα-mediated epigenetic repression. -
Mutpred2: Inferring the Molecular and Phenotypic Impact of Amino Acid Variants
bioRxiv preprint doi: https://doi.org/10.1101/134981; this version posted May 9, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. MutPred2: inferring the molecular and phenotypic impact of amino acid variants Vikas Pejaver1, Jorge Urresti2, Jose Lugo-Martinez1, Kymberleigh A. Pagel1, Guan Ning Lin2, Hyun-Jun Nam2, Matthew Mort3, David N. Cooper3, Jonathan Sebat2, Lilia M. Iakoucheva2, Sean D. Mooney4, and Predrag Radivojac1 1Indiana University, Bloomington, Indiana, U.S.A. 2University of California San Diego, La Jolla, California, U.S.A. 3Cardiff University, Cardiff, U.K. 4University of Washington, Seattle, Washington, U.S.A. Contact: [email protected]; [email protected]; [email protected] Abstract We introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. While its prioritization performance is state-of-the-art, a novel and distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific as- pects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the iden- tification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neu- rodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanism- driven studies of human inherited diseases have the potential to significantly accelerate the discovery of clinically actionable variants. -
And CAND1-Dependent Remodelling of the Budding Yeast SCF Complex
ARTICLE Received 31 Jan 2013 | Accepted 20 Feb 2013 | Published 27 Mar 2013 DOI: 10.1038/ncomms2628 OPEN CSN- and CAND1-dependent remodelling of the budding yeast SCF complex Aleksandra Zemla1, Yann Thomas1, Sylwia Kedziora1, Axel Knebel1, Nicola T Wood1, Gwenae¨l Rabut2 & Thimo Kurz1 Cullin–RING ligases (CRLs) are ubiquitin E3 enzymes with variable substrate-adaptor and -receptor subunits. All CRLs are activated by modification of the cullin subunit with the ubiquitin-like protein Nedd8 (neddylation). The protein CAND1 (Cullin-associated-Nedd8- dissociated-1) also promotes CRL activity, even though it only interacts with inactive ligase complexes. The molecular mechanism underlying this behaviour remains largely unclear. Here, we find that yeast SCF (Skp1–Cdc53–F-box) Cullin–RING complexes are remodelled in a CAND1-dependent manner, when cells are switched from growth in fermentable to non-fermentable carbon sources. Mechanistically, CAND1 promotes substrate adaptor release following SCF deneddylation by the COP9 signalosome (CSN). CSN- or CAND1- mutant cells fail to release substrate adaptors. This delays the formation of new complexes during SCF reactivation and results in substrate degradation defects. Our results shed light on how CAND1 regulates CRL activity and demonstrate that the cullin neddylation– deneddylation cycle is not only required to activate CRLs, but also to regulate substrate specificity through dynamic substrate adaptor exchange. 1 Scottish Institute for Cell Signalling, Protein Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK. 2 CNRS, Universite´ Rennes 1, Institut de Ge´ne´tique et De´veloppement de Rennes, 2 avenue du Professeur Le´on Bernard, CS 34317, Rennes Cedex 35043, France. -
Associated 16P11.2 Deletion in Drosophila Melanogaster
ARTICLE DOI: 10.1038/s41467-018-04882-6 OPEN Pervasive genetic interactions modulate neurodevelopmental defects of the autism- associated 16p11.2 deletion in Drosophila melanogaster Janani Iyer1, Mayanglambam Dhruba Singh1, Matthew Jensen1,2, Payal Patel 1, Lucilla Pizzo1, Emily Huber1, Haley Koerselman3, Alexis T. Weiner 1, Paola Lepanto4, Komal Vadodaria1, Alexis Kubina1, Qingyu Wang 1,2, Abigail Talbert1, Sneha Yennawar1, Jose Badano 4, J. Robert Manak3,5, Melissa M. Rolls1, Arjun Krishnan6,7 & 1234567890():,; Santhosh Girirajan 1,2,8 As opposed to syndromic CNVs caused by single genes, extensive phenotypic heterogeneity in variably-expressive CNVs complicates disease gene discovery and functional evaluation. Here, we propose a complex interaction model for pathogenicity of the autism-associated 16p11.2 deletion, where CNV genes interact with each other in conserved pathways to modulate expression of the phenotype. Using multiple quantitative methods in Drosophila RNAi lines, we identify a range of neurodevelopmental phenotypes for knockdown of indi- vidual 16p11.2 homologs in different tissues. We test 565 pairwise knockdowns in the developing eye, and identify 24 interactions between pairs of 16p11.2 homologs and 46 interactions between 16p11.2 homologs and neurodevelopmental genes that suppress or enhance cell proliferation phenotypes compared to one-hit knockdowns. These interac- tions within cell proliferation pathways are also enriched in a human brain-specific network, providing translational relevance in humans. Our study indicates a role for pervasive genetic interactions within CNVs towards cellular and developmental phenotypes. 1 Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA. 2 Bioinformatics and Genomics Program, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA. -
Kelch-Like Protein 2 Mediates Angiotensin II–With No Lysine 3 Signaling in the Regulation of Vascular Tonus
BASIC RESEARCH www.jasn.org Kelch-Like Protein 2 Mediates Angiotensin II–With No Lysine 3 Signaling in the Regulation of Vascular Tonus Moko Zeniya, Nobuhisa Morimoto, Daiei Takahashi, Yutaro Mori, Takayasu Mori, Fumiaki Ando, Yuya Araki, Yuki Yoshizaki, Yuichi Inoue, Kiyoshi Isobe, Naohiro Nomura, Katsuyuki Oi, Hidenori Nishida, Sei Sasaki, Eisei Sohara, Tatemitsu Rai, and Shinichi Uchida Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan ABSTRACT Recently, the kelch-like protein 3 (KLHL3)–Cullin3 complex was identified as an E3 ubiquitin ligase for with no lysine (WNK) kinases, and the impaired ubiquitination of WNK4 causes pseudohypoaldosteronism type II (PHAII), a hereditary hypertensive disease. However, the involvement of WNK kinase regulation by ubiquitination in situations other than PHAII has not been identified. Previously, we identified the WNK3–STE20/SPS1-related proline/alanine-rich kinase–Na/K/Cl cotransporter isoform 1 phosphoryla- tion cascade in vascular smooth muscle cells and found that it constitutes an important mechanism of vascular constriction by angiotensin II (AngII). In this study, we investigated the involvement of KLHL proteins in AngII-induced WNK3 activation of vascular smooth muscle cells. In the mouse aorta and mouse vascular smooth muscle (MOVAS) cells, KLHL3 was not expressed, but KLHL2, the closest homolog of KLHL3, was expressed. Salt depletion and acute infusion of AngII decreased KLHL2 and increased WNK3 levels in the mouse aorta. Notably, the AngII-induced changes in KLHL2 and WNK3 expression occurred within minutes in MOVAS cells. Results of KLHL2 overexpression and knockdown experiments in MOVAS cells confirmed that KLHL2 is the major regulator of WNK3 protein abundance. -
Targeting the RHOA Pathway Improves Learning and Memory In
bioRxiv preprint doi: https://doi.org/10.1101/2020.05.22.110098; this version posted May 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Targeting the RHOA pathway improves learning and memory in Kctd13 and 16p11.2 deletion mouse models. Authors Sandra MARTIN LORENZO1, Valérie NALESSO1, Claire CHEVALIER1, Marie-Christine BIRLING2, and Yann HERAULT1,2,*. Affiliations 1 Université de Strasbourg, CNRS, INSERM, Institut de Génétique Biologie Moléculaire et Cellulaire, IGBMC - UMR 7104 - Inserm U1258, 1 rue Laurent Fries, 67404 ILLKIRCH cedex 2 Université de Strasbourg, CNRS, INSERM, CELPHEDIA-PHENOMIN-ICS, Institut Clinique de la Souris, 1 rue Laurent Fries, 67404 ILLKIRCH cedex *Corresponding author: Yann HERAULT, [email protected] Keywords: Copy number variation, neurodevelopment, intellectual disability, autism spectrum disorders, KCTD13, mouse model, recognition memory. Running title: Therapeutic effects of fasudil in 16p11.2 models. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.05.22.110098; this version posted May 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. HIGHLIGHTS - Kctd13 haploinsufficiency recapitulates most of the behaviour phenotypes found in the 16p11.2 Del/+ models - Fasudil treatment restores Kctd13 and 16p11.2 Del/+ mutant phenotypes in novel location and novel object recognition memory tests - Fasudil treatment restores the RhoA pathway in Kctd13+/- and 16p11.2 Del/+ models ABSTRACT Gene copy number variants (CNV) have an important role in the appearance of neurodevelopmental disorders. -
CUL3 Gene Cullin 3
CUL3 gene cullin 3 Normal Function The CUL3 gene provides instructions for making a protein called cullin-3. This protein plays a role in the cell machinery that breaks down (degrades) unwanted proteins, called the ubiquitin-proteasome system. Cullin-3 is a core piece of a complex known as an E3 ubiquitin ligase. E3 ubiquitin ligases function as part of the ubiquitin-proteasome system by tagging damaged and excess proteins with molecules called ubiquitin. Ubiquitin serves as a signal to specialized cell structures known as proteasomes, which attach (bind) to the tagged proteins and degrade them. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. This system also regulates the level of proteins involved in several critical cell activities such as the timing of cell division and growth. E3 ubiquitin ligases containing the cullin-3 protein tag proteins called WNK1 and WNK4 with ubiquitin. These proteins are involved in controlling blood pressure in the body. By regulating the amount of WNK1 and WNK4 available, cullin-3 plays a role in blood pressure control. Health Conditions Related to Genetic Changes Pseudohypoaldosteronism type 2 At least 17 mutations in the CUL3 gene can cause pseudohypoaldosteronism type 2 ( PHA2), a condition characterized by high blood pressure (hypertension) and high levels of potassium in the blood (hyperkalemia). These mutations lead to production of an abnormally short cullin-3 protein that is missing a region. Studies show that this change alters the function of the E3 ubiquitin ligase complex. The change leads to impaired degradation of the WNK4 protein, although the exact mechanism is unclear. -
New Strategies to Inhibit KEAP1 and the Cul3-Based E3 Ubiquitin Ligases
Signalling 2013: from Structure to Function 103 New strategies to inhibit KEAP1 and the Cul3-based E3 ubiquitin ligases Peter Canning*1,2 and Alex N. Bullock*1 *Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K. Abstract E3 ubiquitin ligases that direct substrate proteins to the ubiquitin–proteasome system are promising, though largely unexplored drug targets both because of their function and their remarkable specificity. CRLs [Cullin– RING (really interesting new gene) ligases] are the largest group of E3 ligases and function as modular multisubunit complexes constructed around a Cullin-family scaffold protein. The Cul3-based CRLs uniquely assemble with BTB (broad complex/tramtrack/bric-a-brac)` proteins that also homodimerize and perform the role of both the Cullin adapter and the substrate-recognition component of the E3. The most prominent member is the BTB–BACK (BTB and C-terminal Kelch)–Kelch protein KEAP1 (Kelch-like ECH-associated protein 1), a master regulator of the oxidative stress response and a potential drug target for common conditions such as diabetes, Alzheimer’s disease and Parkinson’s disease. Structural characterization of BTB–Cul3 complexes has revealed a number of critical assembly mechanisms, including the binding of an N-terminal Cullin extension to a bihelical ‘3-box’ at the C-terminus of the BTB domain. Improved understanding of the structure of these complexes should contribute significantly to the effort to develop novel therapeutics targeted to CRL3-regulated pathways. Cullin–RING ligases The multisubunit CRLs (Cullin–RING ligases) represent Specific patterns of mono- or poly-ubiquitylation are used the largest class of E3 ligase. -
A High Throughput, Functional Screen of Human Body Mass Index GWAS Loci Using Tissue-Specific Rnai Drosophila Melanogaster Crosses Thomas J
Washington University School of Medicine Digital Commons@Becker Open Access Publications 2018 A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses Thomas J. Baranski Washington University School of Medicine in St. Louis Aldi T. Kraja Washington University School of Medicine in St. Louis Jill L. Fink Washington University School of Medicine in St. Louis Mary Feitosa Washington University School of Medicine in St. Louis Petra A. Lenzini Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Baranski, Thomas J.; Kraja, Aldi T.; Fink, Jill L.; Feitosa, Mary; Lenzini, Petra A.; Borecki, Ingrid B.; Liu, Ching-Ti; Cupples, L. Adrienne; North, Kari E.; and Province, Michael A., ,"A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses." PLoS Genetics.14,4. e1007222. (2018). https://digitalcommons.wustl.edu/open_access_pubs/6820 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Thomas J. Baranski, Aldi T. Kraja, Jill L. Fink, Mary Feitosa, Petra A. Lenzini, Ingrid B. Borecki, Ching-Ti Liu, L. Adrienne Cupples, Kari E. North, and Michael A. Province This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/6820 RESEARCH ARTICLE A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses Thomas J. -
The Cyclin E Regulator Cullin 3 Prevents Mouse
Downloaded from http://www.jci.org on January 11, 2016. http://dx.doi.org/10.1172/JCI41959 Research article The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells Uta Kossatz,1 Kai Breuhahn,2 Benita Wolf,3 Matthias Hardtke-Wolenski,3 Ludwig Wilkens,4 Doris Steinemann,5 Stephan Singer,2 Felicitas Brass,3 Stefan Kubicka,3 Brigitte Schlegelberger,5 Peter Schirmacher,2 Michael P. Manns,3 Jeffrey D. Singer,6 and Nisar P. Malek1,3 1Institute for Molecular Biology, Hannover Medical School, Hannover, Germany. 2Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 3Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 4Institute of Pathology, Nordstadt Krankenhaus, Hannover, Germany. 5Institute for Cellular and Molecular Pathology, Hannover Medical School, Hannover, Germany. 6Department of Biology, Portland State University, Portland, Oregon, USA. Cyclin E is often overexpressed in cancer tissue, leading to genetic instability and aneuploidy. Cullin 3 (Cul3) is a component of the BTB-Cul3-Rbx1 (BCR) ubiquitin ligase that is involved in the turnover of cyclin E. Here we show that liver-specific ablation of Cul3 in mice results in the persistence and massive expansion of hepatic progenitor cells. Upon induction of differentiation, Cul3-deficient progenitor cells underwent sub- stantial DNA damage in vivo and in vitro, thereby triggering the activation of a cellular senescence response that selectively blocked the expansion of the differentiated offspring. Positive selection of undifferentiated progenitor cells required the expression of the tumor suppressor protein p53. Simultaneous loss of Cul3 and p53 in hepatic progenitors turned these cells into highly malignant tumor-initiating cells that formed largely undifferentiated tumors in nude mice.