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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
Ranhui Duan, Yuting Shi, Li Yu, Gehan Zhang, Jia Li, Yunting Lin, Jifeng Guo, Junling Wang, Lu Shen, Hong Jiang, Guanghui Wang, Beisha Tang
Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. For many affected patients, the genetic cause remains undetermined. Through whole-exome sequencing, we identified compound heterozygous mutations in ubiquitin-like modifier activating enzyme 5 gene (UBA5) in two Chinese siblings presenting with ARCA. Moreover, copy number variations in UBA5 or ubiquitin-fold modifier 1 gene (UFM1) were documented with the phenotypes of global developmental delays and gait disturbances in the ClinVar database...
2016: PloS One
Yafei Cai, Wenhu Pi, Satish Sivaprakasam, Xiaobin Zhu, Mingsheng Zhang, Jijun Chen, Levi Makala, Chunwan Lu, Jianchu Wu, Yong Teng, Betty Pace, Dorothy Tuan, Nagendra Singh, Honglin Li
The Ufm1 conjugation system is an ubiquitin-like modification system that consists of Ufm1, Uba5 (E1), Ufc1 (E2), and less defined E3 ligase(s) and targets. The biological importance of this system is highlighted by its essential role in embryogenesis and erythroid development, but the underlying mechanism is poorly understood. UFBP1 (Ufm1 binding protein 1, also known as DDRGK1, Dashurin and C20orf116) is a putative Ufm1 target, yet its exact physiological function and impact of its ufmylation remain largely undefined...
November 2015: PLoS Genetics
Janine van Loon, Abbas Dehghan, Tang Weihong, Stella Trompet, Wendy L McArdle, Folkert F W Asselbergs, Ming-Huei Chen, Lorna M Lopez, Jennifer E Huffman, Frank W G Leebeek, Saonli Basu, David J Stott, Ann Rumley, Ron T Gansevoort, Gail Davies, James J F Wilson, Jacqueline C M Witteman, Xiting Cao, Anton J M de Craen, Stephan J L Bakker, Bruce M Psaty, John M Starr, Albert Hofman, J Wouter Jukema, Ian J Deary, Caroline Hayward, Pim van der Harst, Gordon D O Lowe, Aaron R Folsom, David P Strachan, Nicolas Smith, Moniek P M de Maat, Christopher O'Donnell
Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available...
July 2016: European Journal of Human Genetics: EJHG
Christopher Mark Watson, Laura A Crinnion, Lindsay Gleghorn, William G Newman, Rajkumar Ramesar, Peter Beighton, Gillian A Wallis
BACKGROUND: Beukes hip dysplasia (BHD) is an autosomal dominant disorder of variable penetrance that was originally identified in a large South African family of European origin. BHD is characterised by bilateral dysmorphism of the proximal femur, which results in severe degenerative osteoarthropathy. Previous studies mapped the disorder to a 3.34 Mb region on chromosome 4q35. OBJECTIVE: To fine-map the BHD locus and identify the disease-causing mutation by direct sequencing...
July 2015: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
Qi Pang, Jie Xiong, Xiao-Lei Hu, Jiang-Ping He, Hui-Fang Liu, Guang-Ya Zhang, Yuan-Yuan Li, Feng-Ling Chen
AIM: Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and its underlying mechanism of action in macrophage foam cell formation is poorly understood. Our current study focuses on UFM1 and investigates its role in macrophage foam cell formation. METHODS: Using real-time quantitative PCR (qRT-PCR) and western blot analysis, we first analyzed the UFM1 expression in mouse peritoneal macrophages (MPMs) from ApoE-/- mice in vivo and in human macrophages treated with oxLDL in vitro...
2015: Journal of Atherosclerosis and Thrombosis
M Zhang, X Zhu, Y Zhang, Y Cai, J Chen, S Sivaprakasam, A Gurav, W Pi, L Makala, J Wu, B Pace, D Tuan-Lo, V Ganapathy, N Singh, H Li
The Ufm1 conjugation system is a novel ubiquitin-like modification system, consisting of Ufm1, Uba5 (E1), Ufc1 (E2) and poorly characterized E3 ligase(s). RCAD/Ufl1 (also known as KIAA0776, NLBP and Maxer) was reported to function as a Ufm1 E3 ligase in ufmylation (Ufm1-mediated conjugation) of DDRGK1 and ASC1 proteins. It has also been implicated in estrogen receptor signaling, unfolded protein response (UPR) and neurodegeneration, yet its physiological function remains completely unknown. In this study, we report that RCAD/Ufl1 is essential for embryonic development, hematopoietic stem cell (HSC) survival and erythroid differentiation...
December 2015: Cell Death and Differentiation
Hee Min Yoo, Jong Ho Park, Young Joo Jeon, Chin Ha Chung
Estrogen receptor-α (ERα) is a steroid hormone-sensitive transcription factor that plays a critical role in development of breast cancer. The binding of estrogen to ERα triggers the recruitment of transcriptional co-activators as well as chromatin remodeling factors to estrogen-responsive elements (ERE) of ERα target genes. This process is tightly associated with post-translational modifications (PTMs) of ERα and its co-activators for promotion of transcriptional activation, which leads to proliferation of a large subset of breast tumor cells...
2015: Frontiers in Endocrinology
Xavier Grau-Bové, Arnau Sebé-Pedrós, Iñaki Ruiz-Trillo
The origin of the eukaryotic cell is one of the most important transitions in the history of life. However, the emergence and early evolution of eukaryotes remains poorly understood. Recent data have shown that the last eukaryotic common ancestor (LECA) was much more complex than previously thought. The LECA already had the genetic machinery encoding the endomembrane apparatus, spliceosome, nuclear pore, and myosin and kinesin cytoskeletal motors. It is unclear, however, when the functional regulation of these cellular components evolved...
March 2015: Molecular Biology and Evolution
(no author information available yet)
UFM1 modifies ASC1 to promote ERα transactivation and development of breast cancer.
November 2014: Cancer Discovery
Hui Liu, Ming Gong, Barbara A French, Jun Li, Brittany Tillman, Samuel W French
Promoter CpG island hypermethylation is an important mechanism for inactivating key cellular enzymes that mediate epigenetic processes in hepatitis-related hepatocellular carcinoma (HCC). The ubiquitin-fold modifier 1 (Ufm1) conjugation pathway (Ufmylation) plays an essential role in protein degradation, protein quality control and signal transduction. Previous studies showed that the Ufmylation pathway was downregulated in alcoholic hepatitis (AH), non-alcoholic steatohepatitis (NASH) and in mice fed DDC, resulting in the formation of Mallory-Denk Bodies (MDBs)...
December 2014: Experimental and Molecular Pathology
Hee Min Yoo, Sung Hwan Kang, Jae Yeon Kim, Joo Eun Lee, Min Woo Seong, Seong Won Lee, Seung Hyeun Ka, Yu-Shin Sou, Masaaki Komatsu, Keiji Tanaka, Soon Tae Lee, Dong Young Noh, Sung Hee Baek, Young Joo Jeon, Chin Ha Chung
Biological roles for UFM1, a ubiquitin-like protein, are largely unknown, and therefore we screened for targets of ufmylation. Here we show that ufmylation of the nuclear receptor coactivator ASC1 is a key step for ERα transactivation in response to 17β-estradiol (E2). In the absence of E2, the UFM1-specific protease UfSP2 was bound to ASC1, which maintains ASC1 in a nonufmylated state. In the presence of E2, ERα bound ASC1 and displaced UfSP2, leading to ASC1 ufmylation. Polyufmylation of ASC1 enhanced association of p300, SRC1, and ASC1 at promoters of ERα target genes...
October 23, 2014: Molecular Cell
Shutao Xie
Human Uba5, which contains an adenylation domain and a C-terminal region, is the smallest ubiquitin-like molecule-activating enzyme. The mechanism through which the enzyme recognizes Ufc1 and catalyzes the formation of the Ufc1-Ufm1 complex remains unknown. In this study, Uba5 residues 364-404 were demonstrated to be necessary for the transthiolation of Ufm1 to Ufc1, and Uba5 381-404 was identified to be the minimal region for Ufc1 recognition. The fusion protein between Uba5 381-404 and Ufc1 was cloned, expressed and purified, and exists as a homodimer in solution...
August 2014: Acta Crystallographica. Section F, Structural Biology Communications
James M Gavin, Kara Hoar, Qing Xu, Jingya Ma, Yafang Lin, Jiejin Chen, Wei Chen, Frank J Bruzzese, Sean Harrison, William D Mallender, Nancy J Bump, Michael D Sintchak, Neil F Bence, Ping Li, Lawrence R Dick, Alexandra E Gould, Jesse J Chen
E1 enzymes activate ubiquitin or ubiquitin-like proteins (Ubl) via an adenylate intermediate and initiate the enzymatic cascade of Ubl conjugation to target proteins or lipids. Ubiquitin-fold modifier 1 (Ufm1) is activated by the E1 enzyme Uba5, and this pathway is proposed to play an important role in the endoplasmic reticulum (ER) stress response. However, the mechanisms of Ufm1 activation by Uba5 and subsequent transfer to the conjugating enzyme (E2), Ufc1, have not been studied in detail. In this work, we found that Uba5 activated Ufm1 via a two-step mechanism and formed a binary covalent complex of Uba5∼Ufm1 thioester...
August 15, 2014: Journal of Biological Chemistry
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