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Colleen A McGourty, David Akopian, Carolyn Walsh, Amita Gorur, Achim Werner, Randy Schekman, Diana Bautista, Michael Rape
The ubiquitin ligase CUL3 is an essential regulator of neural crest specification whose aberrant activation has been linked to autism, schizophrenia, and hypertension. CUL3 exerts its roles by pairing with ∼90 distinct substrate adaptors, yet how the different CUL3-complexes are activated is poorly understood. Here, we show that CUL3 and its adaptor KLHL12 require two calcium-binding proteins, PEF1 and ALG2, for recognition of their substrate SEC31. PEF1 and ALG2 form a target-specific co-adaptor that translates a transient rise in cytosolic calcium levels into more persistent SEC31 ubiquitylation, which in turn triggers formation of large COPII coats and promotes collagen secretion...
October 6, 2016: Cell
Neville E Sanjana, Jason Wright, Kaijie Zheng, Ophir Shalem, Pierre Fontanillas, Julia Joung, Christine Cheng, Aviv Regev, Feng Zhang
The noncoding genome affects gene regulation and disease, yet we lack tools for rapid identification and manipulation of noncoding elements. We developed a CRISPR screen using ~18,000 single guide RNAs targeting >700 kilobases surrounding the genes NF1, NF2, and CUL3, which are involved in BRAF inhibitor resistance in melanoma. We find that noncoding locations that modulate drug resistance also harbor predictive hallmarks of noncoding function. With a subset of regions at the CUL3 locus, we demonstrate that engineered mutations alter transcription factor occupancy and long-range and local epigenetic environments, implicating these sites in gene regulation and chemotherapeutic resistance...
September 30, 2016: Science
Siyuan Ding, Nancie Mooney, Bin Li, Marcus R Kelly, Ningguo Feng, Alexander V Loktev, Adrish Sen, John T Patton, Peter K Jackson, Harry B Greenberg
Rotaviruses (RVs) are the leading cause of severe gastroenteritis in young children, accounting for half a million deaths annually worldwide. RV encodes non-structural protein 1 (NSP1), a well-characterized interferon (IFN) antagonist, which facilitates virus replication by mediating the degradation of host antiviral factors including IRF3 and β-TrCP. Here, we utilized six human and animal RV NSP1s as baits and performed tandem-affinity purification coupled with high-resolution mass spectrometry to comprehensively characterize NSP1-host protein interaction network...
October 2016: PLoS Pathogens
Tatsuro Iso, Takafumi Suzuki, Liam Baird, Masayuki Yamamoto
The transcription factor Nrf2 (NF-E2-related-factor-2) is essential for the oxidative and electrophilic stress responses. Keap1 (Kelch-like-ECH-associated-protein-1), an adaptor for a Cullin-3 (Cul3)-based ubiquitin ligase, regulates Nrf2 activity through proteasomal degradation, and acts as a sensor for oxidative and electrophilic stresses. The Keap1-Cul3 complex is a critical regulator of the cellular Nrf2 level, yet quantitative information regarding their endogenous intracellular concentrations in homeostatic conditions and during stress responses is unknown...
October 3, 2016: Molecular and Cellular Biology
Luciano Pirone, Giovanni Smaldone, Carla Esposito, Nicole Balasco, Maxim V Petoukhov, Alessandro Spilotros, Dmitri I Svergun, Sonia Di Gaetano, Luigi Vitagliano, Emilia Maria Pedone
The insomniac protein of Drosophila melanogaster (INC) has a crucial role in sleep homeostasis as flies lacking the inc gene exhibit strikingly reduced and poorly consolidated sleep. Nevertheless, in vitro characterizations of INC biophysical properties and partnerships have not been yet reported. Here we report the heterologous expression of the protein and its characterization using a number of different techniques. Present data indicate that INC is endowed with a remarkable stability, which results from the cooperation of the two protein domains...
September 24, 2016: Biochimie
Cen Zhang, Juan Liu, Grace Huang, Yuhan Zhao, Xuetian Yue, Hao Wu, Jun Li, Junlan Zhu, Zhiyuan Shen, Bruce G Haffty, Wenwei Hu, Zhaohui Feng
Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citrate lyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipid synthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3-RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells...
September 1, 2016: Genes & Development
Thibault Courtheoux, Radoslav I Enchev, Fabienne Lampert, Juan Gerez, Jochen Beck, Paola Picotti, Izabela Sumara, Matthias Peter
Directed cell movement involves spatial and temporal regulation of the cortical microtubule (Mt) and actin networks to allow focal adhesions (FAs) to assemble at the cell front and disassemble at the rear. Mts are known to associate with FAs, but the mechanisms coordinating their dynamic interactions remain unknown. Here we show that the CRL3(KLHL21) E3 ubiquitin ligase promotes cell migration by controlling Mt and FA dynamics at the cell cortex. Indeed, KLHL21 localizes to FA structures preferentially at the leading edge, and in complex with Cul3, ubiquitylates EB1 within its microtubule-interacting CH-domain...
September 19, 2016: Nature Communications
Richard Hollander, Geert Mortier, Koen van Hoeck
: Hyperkalemia in young children is a rare phenomenon and in many cases caused by hemolysis in the specimen due to difficulties in obtaining a sample. However, hyperkalemia can also be a sign of a rare Mendelian syndrome known as familial hyperkalemic hypertension or pseudohypoaldosteronism type II. This disease is characterized by hyperkalemia, hypertension, and mild hyperchloremic metabolic acidosis (with normal anion gap) despite normal glomerular filtration. Full recovery of these abnormalities with thiazide diuretics is essential not to miss the diagnosis of this syndrome...
September 17, 2016: European Journal of Pediatrics
Kathleen M Mulvaney, Jacob P Matson, Priscila F Siesser, Tigist Y Tamir, Dennis Goldfarb, Timothy M Jacobs, Erica W Cloer, Joseph S Harrsion, Cyrus Vaziri, Jeanette G Cook, Michael B Major
KEAP1 is a substrate adaptor protein for a CUL3-based E3 ubiquitin ligase. Ubiquitylation and degradation of the antioxidant transcription factor NRF2 is considered the primary function of KEAP1; however, few other KEAP1 substrates have been identified. Because KEAP1 is altered in a number of human pathologies and has been proposed as a potential therapeutic target therein, we sought to better understand KEAP1 through systematic identification of its substrates. Towards this goal, we combined parallel affinity capture proteomics and candidate-based approaches...
September 12, 2016: Journal of Biological Chemistry
Kun Zhu, Pin-Ji Lei, Lin-Gao Ju, Xiang Wang, Kai Huang, Bo Yang, Changwei Shao, Yuan Zhu, Gang Wei, Xiang-Dong Fu, Lianyun Li, Min Wu
Trimethylation of histone H3K36 is a chromatin mark associated with active gene expression, which has been implicated in coupling transcription with mRNA splicing and DNA damage response. SETD2 is a major H3K36 trimethyltransferase, which has been implicated as a tumor suppressor in mammals. Here, we report the regulation of SETD2 protein stability by the proteasome system, and the identification of SPOP, a key subunit of the CUL3 ubiquitin E3 ligase complex, as a SETD2-interacting protein. We demonstrate that SPOP is critically involved in SETD2 stability control and that the SPOP/CUL3 complex is responsible for SETD2 polyubiquitination both in vivo and in vitro ChIP-Seq analysis and biochemical experiments demonstrate that modulation of SPOP expression confers differential H3K36me3 on SETD2 target genes, and induce H3K36me3-coupled alternative splicing events...
September 9, 2016: Nucleic Acids Research
C Rafael, W Abdel Khalek, I Kouranti, E Clauser, X Jeunemaitre, J Hadchouel
OBJECTIVE: Familial Hyperkalemic Hypertension (FHHt) is caused by mutations in WNK1, WNK4, KLHL3 or CUL3 (cullin-3). Patients with CUL3 mutation display a more severe phenotype. The mechanisms associated with this severity remain unclear. DESIGN AND METHOD: All CUL3 mutations result in the skipping of exon 9. We have generated a mouse model of "Cul3-FHHt" by deleting Cul3 exon 9. RESULTS: RT-PCR proved that the exon skipping occurred as expected in the kidney of Cul3+/d9 mice...
September 2016: Journal of Hypertension
Yongxing Zhang, Hong Fan, Shuo Fang, Lin Wang, Li Chen, Yulin Jin, Wei Jiang, Zongwu Lin, Yu Shi, Cheng Zhan, Qun Wang
BACKGROUND: Recent studies have reported an abnormally high alteration rate in the nuclear factor erythroid 2-like 2 (NFE2L2)/kelch-like ECH-associated protein 1 (KEAP1)/cullin 3 (CUL3) pathway. But the status of this pathway in Chinese patients with lung squamous cell carcinoma (SqCC) has not been thoroughly studied, and there are many uncertainties regarding the expression of pathway intermediates. METHODS: cDNA sequencing and TaqMan qRT-PCR were carried out in paired cancer and adjacent normal samples obtained from 100 Chinese patients with lung SqCC...
July 2016: Journal of Thoracic Disease
Frauke Coppieters, Giulia Ascari, Katharina Dannhausen, Konstantinos Nikopoulos, Frank Peelman, Marcus Karlstetter, Mingchu Xu, Cécile Brachet, Isabelle Meunier, Miltiadis K Tsilimbaris, Chrysanthi Tsika, Styliani V Blazaki, Sarah Vergult, Pietro Farinelli, Thalia Van Laethem, Miriam Bauwens, Marieke De Bruyne, Rui Chen, Thomas Langmann, Ruifang Sui, Françoise Meire, Carlo Rivolta, Christian P Hamel, Bart P Leroy, Elfride De Baere
Inherited retinal dystrophies (iRDs) are a group of genetically and clinically heterogeneous conditions resulting from mutations in over 250 genes. Here, homozygosity mapping and whole-exome sequencing (WES) in a consanguineous family revealed a homozygous missense mutation, c.973C>T (p.His325Tyr), in RCBTB1. In affected individuals, it was found to segregate with retinitis pigmentosa (RP), goiter, primary ovarian insufficiency, and mild intellectual disability. Subsequent analysis of WES data in different cohorts uncovered four additional homozygous missense mutations in five unrelated families in whom iRD segregates with or without syndromic features...
August 4, 2016: American Journal of Human Genetics
Meena Murthy, Thimo Kurz, Kevin M O'Shaughnessy
Familial hyperkalemic hypertension (FHHt) is a rare inherited form of salt-dependent hypertension caused by mutations in proteins that regulate the renal Na(+)-Cl(-) cotransporter NCC Mutations in four genes have been reported to cause FHHt including CUL3 (Cullin3) that encodes a component of a RING E3 ligase. Cullin-3 binds to WNK kinase-bound KLHL3 (the substrate recognition subunit of the ubiquitin ligase complex) to promote ubiquitination and proteasomal degradation of WNK kinases. Deletion of exon 9 from CUL3 (affecting residues 403-459, CUL3(Δ403-459)) causes a severe form of FHHt (PHA2E) that is recapitulated closely in a knock-in mouse model...
July 2016: Physiological Reports
A Bruel, R Vargas-Poussou, X Jeunemaitre, A Labbe, E Merlin, L Bessenay
Gordon's syndrome, or type II pseudo-hypoaldosteronism, is a rare cause of arterial hypertension in children. However, it is important to diagnose this syndrome because of the spectacular efficacy of thiazide diuretics. The typical clinical picture of Gordon syndrome includes, apart from arterial hypertension and dyskaliemia, hyperchloremia metabolic acidosis, hypercalciuria, a low rate of renin, and most frequently, a normal or high rate of aldosterone. Dental abnormalities and growth retardation can also be associated...
August 2016: Archives de Pédiatrie: Organe Officiel de la Sociéte Française de Pédiatrie
Hui Liu, Xiaomeng Liu, Li Wang, Nan Sheng
Populations with obesity or overweight have a high incidence of infertility. We hypothesised that brown adipose tissue (BAT) transplantation can attenuate the impairment of male fertility caused by diet-induced obesity. BATs were transplanted from male donor mice into age and sex matched recipient mice fed high-fat diets (HFD). Sperm motility experiment was conducted after surgical procedure. X-ray computed tomography scanning, biochemical assay, real-time PCR and western blot analysis were performed. BAT transplantation reduced body fat and epididymal fat mass, as well as triglycerides (TG) content in testis and epididymis and total cholesterol (TCHO) contents in epididymis compared with the HFD group...
June 27, 2016: Obesity Research & Clinical Practice
Yangzhou Liu, Ning Han, Qinchuan Li, Zengchun Li
The present study aimed to investigate the regulatory mechanisms underlying sepsis progression in patients with tumor necrosis factor (TNF)-α genetic variations. The GSE5760 expression profile data, which was downloaded from the Gene Expression Omnibus database, contained 30 wild-type (WT) and 28 mutation (MUT) samples. Differentially expressed genes (DEGs) between the two types of samples were identified using the Student's t-test, and the corresponding microRNAs (miRNAs) were screened using WebGestalt software...
July 2016: Experimental and Therapeutic Medicine
Josiane Alves França, Marina Gonçalves Diniz, Vanessa Fátima Bernardes, Raíssa Cristina Costa-Silva, Renan Pedra Souza, Ricardo Santiago Gomez, Carolina Cavaliéri Gomes
BACKGROUND: Cohesin complex is responsible for sister chromatid cohesion. STAG1/STAG2 is part of the complex, which is regulated by PDS5B. Alterations in these genes were described in tumors. PDS5B is a negative regulator of cell proliferation. We aimed to assess molecular alterations in these genes in oral squamous cell carcinoma (OSCC) and predict their expression by the expression of 84 cell cycle genes. In addition, we investigated whether pds5b protein expression impacted ki-67 and p53 immunopositivity...
June 24, 2016: Journal of Oral Pathology & Medicine
Jian Wang, Zi-Hua Zhu, Hong-Bin Yang, Ye Zhang, Xiang-Ning Zhao, Min Zhang, Ying-Bin Liu, Ying-Ying Xu, Qun-Ying Lei
Cullin 3 (CUL3) serves as a scaffold protein and assembles a large number of ubiquitin ligase complexes. It is involved in multiple cellular processes and plays a potential role in tumor development and progression. In this study, we demonstrate that CUL3 targets methionine adenosyltransferase IIα (MAT IIα) and promotes its proteasomal degradation through the ubiquitylation-mediated pathway. MAT IIα is a key enzyme in methionine metabolism and is associated with uncontrolled cell proliferation in cancer...
July 2016: FEBS Journal
Hsin-Yi Chen, Ruey-Hwa Chen
Cullin-RING ubiquitin ligases are the largest E3 ligase family in eukaryotes and are multiprotein complexes. In these complexes, the Cullin protein serves as a scaffold to connect two functional modules of the ligases, the catalytic subunit and substrate-binding subunit. To date, eight members of the Cullin family proteins have been identified. In the Cul3 ubiquitin ligases, Bric-a-brac/Tramtrack/Broad complex (BTB) domain-containing proteins function as a bridge to connect Cul3 and substrates. While the BTB domain is responsible for Cul3 binding, these proteins usually contain an additional domain for substrate interaction, such as MATH, kelch, Zn finger, and PAM, Highwire, and RPM-1 (PHR domain)...
2016: Frontiers in Oncology
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