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Ming Su, Zhihong Yue, Hui Wang, Mei Jia, Congxia Bai, Wei Qiu, Jingzhou Chen
Vascular remodeling is a key process leading to arterial stenosis. Ufmylation, a novel ubiquitin-like modification, was observed to be associated with many biological processes. However, whether ufmylation is involved in the regulation of vascular remodeling remains unclear. Therefore, the present study focused on the role of ufmylation in vascular remodeling. Mouse femoral artery guidewire injury models were used for inducing vascular remodeling. We found that the expression of Ufm1 was upregulated in hyperplastic neointima...
February 20, 2018: DNA and Cell Biology
Mingjin Zou, Jing Wang, Jidong Gao, Hui Han, Yi Fang
The incidence of breast cancer has been increasing in China and the age of breast cancer onset is earlier compared with Western countries. Compounds commonly used in Traditional Chinese Medicine (TCM) are an important source of anticancer drugs. Ginseng is one of the most common medicines used in TCM. Ginsenosides, which are saponins found in the ginseng plant, are the major active components responsible for the chemopreventive effects of ginseng in cancer. However, the mechanisms by which ginsenosides exert their anticancer effects remain elusive...
March 2018: Oncology Letters
Bayan Mashahreh, Fouad Hassouna, Nadine Soudah, Einav Cohen-Kfir, Roi Strulovich, Yoni Haitin, Reuven Wiener
All ubiquitin-like proteins (UBLs) undergo an activation process before their conjugation to target proteins. Although the steps required for the activation of UBLs are conserved and common to all UBLs, we have previously shown that the activation of the UBL, ubiquitin fold modifier 1 (UFM1) by the E1, Ufm1 modifier-activating enzyme 5 (UBA5) is executed in a trans-binding mechanism, not observed in any other E1. In this study, we explored the necessity of that mechanism for UFM1 activation and found that it is needed not only for UFM1 binding to UBA5 but also for stabilizing the UBA5 homodimer...
January 2, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Hainan Zheng, Mengyun Wang, Chengcheng Zhao, Shanli Wu, Peifeng Yu, Yan Lü, Tiedong Wang, Yongxing Ai
Deubiquitinases (DUBs) are essential regulators of intracellular processes involving ubiquitin (Ub) modification. The human DUB ubiquitin-specific protease 1 (hUSP1) interacts with human USP-associated factor 1 (hUAF1), and helps to regulate processes such as DNA damage repair. Previously, we identified a chicken USP1 homologue (chUSP1) during an investigation into the properties of Marek's disease virus (MDV). However, chUSP1's deubiquitination activity, interaction with chUAF1, and substrate specificity remained unknown...
2017: PloS One
Eline M C Hamilton, Enrico Bertini, Luba Kalaydjieva, Bharti Morar, Dana Dojčáková, Judy Liu, Adeline Vanderver, Julian Curiel, Claudia M Persoon, Daria Diodato, Lorenzo Pinelli, Nathalie L van der Meij, Barbara Plecko, Susan Blaser, Nicole I Wolf, Quinten Waisfisz, Truus E M Abbink, Marjo S van der Knaap
OBJECTIVE: To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations. METHODS: We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression. RESULTS: Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy...
October 24, 2017: Neurology
M Di Rocco, M Rusmini, F Caroli, A Madeo, M Bertamino, G Marre-Brunenghi, I Ceccherini
Beukes Hip Dysplasia is an autosomal dominant disease which has to date been described only in a large South African family of Dutch origin. The patients presented with progressive epiphyseal dysplasia limited to femoral capital epiphysis and their height was not significantly reduced. A unique variant of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 (UFSP2) gene (c.868T>C) has been reported in all individuals from Beukes family with clinical and radiological diagnosis of Beukes Hip Dysplasia...
September 11, 2017: Clinical Genetics
Yuan-Yuan Li, Guang-Ya Zhang, Jiang-Ping He, Dan-Dan Zhang, Xiang-Xin Kong, Hui-Min Yuan, Feng-Ling Chen
Endothelial cell dysfunction and inflammatory responses are important early contributors to the occurrence and development of atherosclerosis (AS), which still remains to be decoded. Ubiquitin-fold modifier 1 (Ufm1) is a new member of the ubiquitin-like protein family, and its biological function remains largely unknown, particularly in endothelial cell injury and inflammatory responses. In the present study, we showed that Ufm1 was highly expressed in both the nucleus and cytoplasm of human umbilical vein endothelial cells (HUVECs)...
May 2017: International Journal of Molecular Medicine
Prasanth Padala, Walaa Oweis, Bayan Mashahreh, Nadine Soudah, Einav Cohen-Kfir, Emily A Todd, Christopher E Berndsen, Reuven Wiener
The modification of proteins by ubiquitin-fold modifier 1 (UFM1) is implicated in many human diseases. Prior to conjugation, UFM1 undergoes activation by its cognate activating enzyme, UBA5. UBA5 is a non-canonical E1 activating enzyme that possesses an adenylation domain but lacks a distinct cysteine domain. Binding of UBA5 to UFM1 is mediated via an amino acid sequence, known as the UFM1-interacting sequence (UIS), located outside the adenylation domain that is required for UFM1 activation. However, the precise boundaries of the UIS are yet not clear and are still under debate...
March 30, 2017: Scientific Reports
Allison M Roberts, David K Miyamoto, Tucker R Huffman, Leslie A Bateman, Ashley N Ives, David Akopian, Martin J Heslin, Carlo M Contreras, Michael Rape, Christine F Skibola, Daniel K Nomura
Chemical genetic screening of small-molecule libraries has been a promising strategy for discovering unique and novel therapeutic compounds. However, identifying the targets of lead molecules that arise from these screens has remained a major bottleneck in understanding the mechanism of action of these compounds. Here, we have coupled the screening of a cysteine-reactive fragment-based covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform to rapidly couple the discovery of lead small molecules that impair pancreatic cancer pathogenicity with the identification of druggable hotspots for potential cancer therapy...
April 21, 2017: ACS Chemical Biology
S Aslibekyan, A N Do, H Xu, S Li, M R Irvin, D Zhi, H K Tiwari, D M Absher, A R Shuldiner, T Zhang, W Chen, K Tanner, C Hong, B D Mitchell, G Berenson, D K Arnett
BACKGROUND AND AIMS: Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood. METHODS AND RESULTS: We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 991)...
March 2017: Nutrition, Metabolism, and Cardiovascular Diseases: NMCD
Jiang Liu, Ying Wang, Lizhi Song, Linghua Zeng, Weiwei Yi, Ting Liu, Huanzhen Chen, Miao Wang, Zhenyu Ju, Yu-Sheng Cong
Disturbance of endoplasmic reticulum (ER) homoeostasis induces ER stress and leads to activation of the unfolded protein response (UPR), which is an adaptive reaction that promotes cell survival or triggers apoptosis, when homoeostasis is not restored. DDRGK1 is an ER membrane protein and a critical component of the ubiquitin-fold modifier 1 (Ufm1) system. However, the functions and mechanisms of DDRGK1 in ER homoeostasis are largely unknown. Here, we show that depletion of DDRGK1 induces ER stress and enhances ER stress-induced apoptosis in both cancer cells and hematopoietic stem cells (HSCs)...
January 27, 2017: Nature Communications
Camille Miller, Yafei Cai, Tadd Patton, Sarai Hacker Graves, Honglin Li, Maria Eugenia Sabbatini
Alcoholism causes an imbalance of endoplasmic reticulum (ER) homeostasis in pancreatic acini. In those cells, the ER is involved in the synthesis and folding of pancreatic enzymes. Ubiquitin-fold modifier 1 (Ufm1) is part of a novel ubiquitin-like modification system involved in maintaining ER homeostasis. Among the components of the Ufm1 system, Regulator of C53 and DDRGK1 (RCAD) has recently been identified as a Ufm1-specific E3 ligase that promotes ufmylation of DDRGK1, an RCAD-interacting protein. We determined the importance of RCAD in the proper synthesis and secretion of pancreatic enzymes using mice with genetically deleted RCAD...
March 1, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
Lucia Pirone, Wendy Xolalpa, Jón Otti Sigurðsson, Juanma Ramirez, Coralia Pérez, Monika González, Ainara Ruiz de Sabando, Félix Elortza, Manuel S Rodriguez, Ugo Mayor, Jesper V Olsen, Rosa Barrio, James D Sutherland
Post-translational modification by ubiquitin and ubiquitin-like proteins (UbLs) is fundamental for maintaining protein homeostasis. Efficient isolation of UbL conjugates is hampered by multiple factors, including cost and specificity of reagents, removal of UbLs by proteases, distinguishing UbL conjugates from interactors, and low quantities of modified substrates. Here we describe bioUbLs, a comprehensive set of tools for studying modifications in Drosophila and mammals, based on multicistronic expression and in vivo biotinylation using the E...
January 18, 2017: Scientific Reports
Estelle Colin, Jens Daniel, Alban Ziegler, Jamal Wakim, Aurora Scrivo, Tobias B Haack, Salim Khiati, Anne-Sophie Denommé, Patrizia Amati-Bonneau, Majida Charif, Vincent Procaccio, Pascal Reynier, Kyrieckos A Aleck, Lorenzo D Botto, Claudia Lena Herper, Charlotte Sophia Kaiser, Rima Nabbout, Sylvie N'Guyen, José Antonio Mora-Lorca, Birgit Assmann, Stine Christ, Thomas Meitinger, Tim M Strom, Holger Prokisch, Antonio Miranda-Vizuete, Georg F Hoffmann, Guy Lenaers, Pascale Bomont, Eva Liebau, Dominique Bonneau
Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure...
September 1, 2016: American Journal of Human Genetics
Mikko Muona, Ryosuke Ishimura, Anni Laari, Yoshinobu Ichimura, Tarja Linnankivi, Riikka Keski-Filppula, Riitta Herva, Heikki Rantala, Anders Paetau, Minna Pöyhönen, Miki Obata, Takefumi Uemura, Thomas Karhu, Norihisa Bizen, Hirohide Takebayashi, Shane McKee, Michael J Parker, Nadia Akawi, Jeremy McRae, Matthew E Hurles, Outi Kuismin, Mitja I Kurki, Anna-Kaisa Anttonen, Keiji Tanaka, Aarno Palotie, Satoshi Waguri, Anna-Elina Lehesjoki, Masaaki Komatsu
The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort...
September 1, 2016: American Journal of Human Genetics
Sara R da Silva, Stacey-Lynn Paiva, Matthew Bancerz, Mulu Geletu, Andrew M Lewis, Jijun Chen, Yafei Cai, Julie L Lukkarila, Honglin Li, Patrick T Gunning
Protein conjugation with ubiquitin and ubiquitin-like small molecules, such as UFM1, is important for promoting cancer cell survival and proliferation. Herein, the development of the first selective micromolar inhibitor of the UBA5 E1 enzyme that initiates UFM1 protein conjugation is described. This organometallic inhibitor incorporates adenosine and zinc(II)cyclen within its core scaffold and inhibits UBA5 noncompetitively and selectively over other E1 enzymes and a panel of human kinases. Furthermore, this compound selectively impedes the cellular proliferation (above 50μM) of cancer cells containing higher levels of UBA5...
September 15, 2016: Bioorganic & Medicinal Chemistry Letters
Byung Hak Ha, Kyung Hee Kim, Hee Min Yoo, Weontae Lee, Eunice EunKyeong Kim
Ubiquitin-fold modifier 1 (Ufm1) specific protease (UfSP) is a novel cysteine protease that activates Ufm1 from its precursor by processing the C-terminus to expose the conserved Gly necessary for substrate conjugation and de-conjugates Ufm1 from the substrate. There are two forms: UfSP1 and UfSP2, the later with an additional domain at the N-terminus. Ufm1 and both the conjugating and deconjugating enzymes are highly conserved. However, in Caenorhabditis elegans there is one UfSP which has extra 136 residues at the N terminus compared to UfSP2...
August 5, 2016: Biochemical and Biophysical Research Communications
Ying Wei, Xingzhi Xu
Ubiquitin-fold modifier 1 (UFM1) is one of the newly-identified ubiquitin-like proteins. Similar to ubiquitin, UFM1 is conjugated to its target proteins by a three-step enzymatic reaction. The UFM1-activating enzyme, ubiquitin-like modifier-activating enzyme 5 (UBA5), serves as the E1 to activate UFM1; UFM1-conjugating enzyme 1 (UFC1) acts as the E2 to transfer the activated UFM1 to the active site of the E2; and the UFM1-specific ligase 1 (UFL1) acts as the E3 to recognize its substrate, transfer, and ligate the UFM1 from E2 to the substrate...
June 2016: Genomics, Proteomics & Bioinformatics
Yafei Cai, Nagendra Singh, Honglin Li
Protein modification by ubiquitin (Ub) and ubiquitin-like (Ubl) proteins plays a pivotal role in a wide range of cellular functions and signaling pathways. The Ufm1 conjugation system is a novel ubiquitin-like system that consists of Ufm1, Uba5 (E1), Ufc1 (E2), and less defined E3 ligase(s) and targets. Despite its discovery more than a decade ago, its biological functions and working mechanism remains poorly understood. Recent genetic studies using knockout mouse models provide unambiguous evidence for the indispensable role of the Ufm1 system in animal development and hematopoiesis, especially erythroid development...
June 2016: Experimental Hematology
Sabrina Habisov, Jessica Huber, Yoshinobu Ichimura, Masato Akutsu, Natalia Rogova, Frank Loehr, David G McEwan, Terje Johansen, Ivan Dikic, Volker Doetsch, Masaaki Komatsu, Vladimir V Rogov, Vladimir Kirkin
The covalent conjugation of ubiquitin-fold modifier 1 (UFM1) to proteins generates a signal that regulates transcription, response to cell stress, and differentiation. Ufmylation is initiated by ubiquitin-like modifier activating enzyme 5 (UBA5), which activates and transfers UFM1 to ubiquitin-fold modifier-conjugating enzyme 1 (UFC1). The details of the interaction between UFM1 and UBA5 required for UFM1 activation and its downstream transfer are however unclear. In this study, we described and characterized a combined linear LC3-interacting region/UFM1-interacting motif (LIR/UFIM) within the C terminus of UBA5...
April 22, 2016: Journal of Biological Chemistry
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