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Huan Chen, Zhaowei Xu, Xiahui Li, Yangyang Yang, Bowen Li, Yanan Li, Kangkai Xia, Jian Wang, Shujing Li, Miao Wang, Huijian Wu
α-catenin has been demonstrated to suppress several different types of cancers. Here we demonstrate that α-catenin is modified by SUMO protein, which covalently binds α-catenin at the carboxy terminus at lysine 870. Substitution of lysine 870 with arginine completely abolishes α-catenin SUMOylation. This modification can be removed by SENP1. However, α-catenin SUMOylation does not affect its stability and subcellular localization. In addition, we observed that the SUMOylation-deficient α-catenin mutant has a reduced interaction with IκBα which prevents subsequent ubiquitination of IκBα, and therefore a reduced suppression of expression of the NF-κB target genes TNF-α, IL-8, VEGF, and uPA...
March 13, 2018: Oncogenesis
Qingbo Chen, Lei Huang, Dongning Pan, Lihua J Zhu, Yong-Xu Wang
Transcriptional co-activator Prdm16 controls brown fat development and white fat browning, but how this thermogenic function is modulated post-translationally is poorly understood. Here, we report that Cbx4, a Polycomb group protein, is a SUMO E3 ligase for Prdm16 and that Cbx4-mediated sumoylation of Prdm16 is required for thermogenic gene expression. Cbx4 expression is enriched in brown fat and is induced in adipose tissue by acute cold exposure. Sumoylation of Prdm16 at lysine 917 by Cbx4 blocks its ubiquitination-mediated degradation, thereby augmenting its stability and thermogenic function...
March 13, 2018: Cell Reports
Mohamed Ali Maroui, Ghizlane Maarifi, Francis P McManus, Frederic Lamoliatte, Pierre Thibault, Mounira K Chelbi-Alix
We report that interferon (IFN) a treatment at short and long periods increases the global cellular SUMOylation and requires the presence of the SUMO E3 ligase promyelocytic leukemia protein (PML), the organizer of PML nuclear bodies (NBs). Several PML isoforms (PMLI-PMLVII) derived from a single PML gene by alternative splicing, share the same N-terminal region but differ in their C-terminal sequences. Introducing each of the human PML isoform in PML-negative cells revealed that enhanced SUMOylation in response to IFN is orchestrated by PMLIII and PMLIV...
March 13, 2018: Molecular & Cellular Proteomics: MCP
Jeremy M Henley, Ruth E Carmichael, Kevin A Wilkinson
Post-translational modification of substrate proteins by SUMO conjugation regulates a diverse array of cellular processes. While predominantly a nuclear protein modification, there is a growing appreciation that SUMOylation of proteins outside the nucleus plays direct roles in controlling synaptic transmission, neuronal excitability, and adaptive responses to cell stress. Furthermore, alterations in protein SUMOylation are observed in a wide range of neurological and neurodegenerative diseases, and several extranuclear disease-associated proteins have been shown to be directly SUMOylated...
March 9, 2018: Trends in Neurosciences
Miriam A Kael, Daniel K Weber, Frances Separovic, Marc-Antoine Sani
The cleavage of the amyloid precursor protein by β- and γ-secretases is a key event in Alzheimer's disease. A fusion protein was constructed to investigate the cleavage rate and aggregation kinetics of amyloid-beta (1-40) (Aβ(1-40)) peptides. The peptide was expressed with a Small Ubiquitin-Like Modifier (SUMO) on the N-terminus and cleaved by a SUMO protease Ulp1. The time course of the cleavage reaction was monitored by SDS-PAGE gel with 100:1 or 1000:1 SUMO-Aβ(1-40) to Ulp1 molar ratio and in the presence of brain total lipid extract unilamellar vesicles...
March 8, 2018: Biochimica et Biophysica Acta
Fang Qiu, Changjiang Dong, Yanxin Liu, Xiaoqi Shao, Di Huang, Yanna Han, Bing Wang, Yanli Liu, Rong Huo, Petro Paulo, Zhiren Zhang, Dan Zhao, Wen-Feng Chu
BACKGROUND AND PURPOSE: Protein modification by small ubiquitin-like modifier (SUMO) plays a critical role in the pathogenesis of heart diseases. The present study was designed to determine whether ginkgolic acid (GA) as a SUMO-1 inhibitor exerts an inhibitory effect on cardiac fibrosis induced by myocardial infarction (MI). EXPERIMENTAL APPROACH: GA was delivered by osmotic pumps in MI mice. Masson staining, electron microscopy (EM) and echocardiography were used to assess cardiac fibrosis, ultrastructure and function...
March 7, 2018: Toxicology and Applied Pharmacology
Srikanth Appikonda, Kaushik N Thakkar, Parantu K Shah, Sharon Y R Dent, Jannik N Andersen, Michelle Craig Barton
Proteins with domains that recognize and bind post-translational modifications (PTMs) of histones are collectively termed epigenetic readers. Numerous interactions between specific reader protein domains and histone PTMs and their regulatory outcomes have been reported, but little is known about how reader proteins may in turn be modulated by these interactions. Tripartite motif-containing protein 24 (TRIM24) is a histone reader aberrantly expressed in multiple cancers. Here, our investigation revealed functional crosstalk between histone acetylation and TRIM24 SUMOylation...
March 9, 2018: Journal of Biological Chemistry
Christine C Lee, Bing Li, Hongtao Yu, Michael J Matunis
The Anaphase Promoting Complex/Cyclosome (APC/C) is a ubiquitin E3 ligase that functions as the gatekeeper to mitotic exit. APC/C activity is controlled by an interplay of multiple pathways during mitosis, including the spindle assembly checkpoint (SAC), that are not yet fully understood. Here, we show that sumoylation of the APC4 subunit of the APC/C peaks during mitosis and is critical for timely APC/C activation and anaphase onset. We have also identified a functionally important SUMO interacting motif in the cullin-homology domain of APC2 located near the APC4 sumoylation sites and APC/C catalytic core...
March 8, 2018: ELife
Dapeng Chen, Fabio Gomes, Dulith Abeykoon, Betsegaw Lemma, Yan Wang, David Fushman, Catherine Fenselau
Post-translational modifications by the covalent attachment of Rub1 (NEDD8), ubiquitin, SUMO, and other small signaling proteins have profound impacts on the functions and fates of cellular proteins. Investigations of the relationship of these bioactive structures and their functions are limited by analytical methods that are scarce and tedious. A novel strategy is reported here for the analysis of branched proteins by top-down mass spectrometry and illustrated by application to four recombinant proteins and one synthetic peptide modified by covalent bonds with ubiquitin or Rub1...
March 7, 2018: Analytical Chemistry
Jing Cao, Xiao-Ming Liu, Li-Lin Huang, Li Wang, Xiao-Fei Jiao, Li-Jun Huo
In the mammalian ovary, >99% follicles fail to ovulate due to apoptosis in granulosa cells. Aurora B, a core subunit enzyme of the chromosomal passenger complex, exerts a crucial role in microtubule‑kinetochore attachment, and has been reported to be modified by small ubiquitin‑related modifier (SUMO) proteins. However, the details of how Aurora B and its SUMOylation impact on follicular development have yet to be fully elucidated. The aim of the present study was to explore the roles, and possible molecular mechanism, of Aurora B and its SUMOylation in the granulosa cells of the mouse follicle...
March 7, 2018: International Journal of Molecular Medicine
Deanne H Hryciw
Preeclampsia (PE), which complicates ∼14% of pregnancies worldwide (Peters & Flack, 2004), can lead to significant maternal morbidity, fetal and neonatal morbidity and premature birth. This article is protected by copyright. All rights reserved.
March 6, 2018: Journal of Physiology
Louise Dubuisson, Florence Lormières, Stefania Fochi, Jocelyn Turpin, Amandine Pasquier, Estelle Douceron, Anaïs Oliva, Ali Bazarbachi, Valérie Lallemand-Breitenbach, Hugues De Thé, Chloé Journo, Renaud Mahieux
Since the identification of the antisense protein of HTLV-2 (APH-2) and the demonstration that APH-2 mRNA is expressed in vivo in most HTLV-2 carriers, much effort has been dedicated to the elucidation of similarities and/or differences between APH-2 and HBZ, the antisense protein of HTLV-1. Similar to HBZ, APH-2 negatively regulates HTLV-2 transcription. However, it does not promote cell proliferation. In contrast to HBZ, APH-2 half-life is very short. Here, we show that APH-2 is addressed to PML nuclear bodies in T-cells, as well as in different cell types...
March 6, 2018: Oncogene
Jason Liang, Bin-Zhong Li, Alexander P Tan, Richard D Kolodner, Christopher D Putnam, Huilin Zhou
Mms21, a subunit of the Smc5/6 complex, possesses an E3 ligase activity for the Small Ubiquitin-like MOdifier (SUMO). Here we show that the mms21-CH mutation, which inactivates Mms21 ligase activity, causes increased accumulation of gross chromosomal rearrangements (GCRs) selected in the dGCR assay. These dGCRs are formed by non-allelic homologous recombination between divergent DNA sequences mediated by Rad52-, Rrm3- and Pol32-dependent break-induced replication. Combining mms21-CH with sgs1Δ caused a synergistic increase in GCRs rates, indicating the distinct roles of Mms21 and Sgs1 in suppressing GCRs...
March 5, 2018: PLoS Genetics
Calvin Jon Antolin Leonen, Esha Upadhyay, Champak Chatterjee
Reversible post-translational modifications of histone proteins in eukaryotic chromatin are closely tied to gene function and cellular development. Specific combinations of histone modifications, or marks, are implicated in distinct DNA-templated processes mediated by a range of chromatin-associated enzymes that install, erase and interpret the histone code. Mechanistic studies of the precise biochemical relationship between sets of marks and their effects on chromatin function are significantly complicated by the dynamic nature and heterogeneity of marks in cellular chromatin...
February 26, 2018: Current Opinion in Chemical Biology
Yuichi Sakata, Tsuyoshi Ushigami, Kazushi Anzawa, Takashi Mochizuki
Trichophyton tonsurans, a major pathogen of tinea capitis and tinea corporis, has been isolated from players of contact sports in Japan. To understand the contemporary epidemic in Japan, the molecular types of 208 strains isolated between 2011 and 2015 were determined. Of these, 142 were isolated from practitioners of judo, 28 from wrestlers, seven from sumo wrestlers, and 31 from individuals with unknown backgrounds. Based on length polymorphisms of the non-transcribed spacer (NTS) region of the ribosomal RNA gene, these 208 strains could be divided into three subtypes, NTS I(204; 98...
February 28, 2018: Japanese Journal of Infectious Diseases
Shamini Vijayakumaran, Dean L Pountney
Protein homeostasis is essential for the wellbeing of several cellular systems. Post-translational modifications (PTM) coordinate various pathways in response to abnormal aggregation of proteins in neurodegenerative disease states. In the presence of accumulating misfolded proteins and toxic aggregates, the small ubiquitin-like modifier (SUMO) is associated with various substrates, including chaperones and other recruited factors, for refolding and for clearance via proteolytic systems, such as the ubiquitin-proteasome pathway (UPS), chaperone-mediated autophagy (CMA) and macroautophagy...
February 25, 2018: Neurotoxicology
Hayeon Baik, Mathias Boulanger, Moshen Hosseini, Julie Kowalczyk, Sonia Zaghdoudi, Tamara Salem, Jean Emmanuel Sarry, Yosr Hicheri, Guillaume Cartron, Marc Piechaczyk, Guillaume Bossis
Differentiation therapies using all-trans retinoic acid (ATRA) are highly efficient at treating acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML). However, their efficacy, if any, is limited in the case of non-APL AML. We report here that inhibition of SUMOylation, a post-translational modification related to ubiquitination, restores the pro-differentiation and anti-proliferative activities of retinoids in non-APL AML. Controlled inhibition of SUMOylation with pharmacological inhibitors 2-D08 or anacardic acid, or via overexpression of SENP deSUMOylases, enhanced the ATRA-induced expression of key genes involved in differentiation, proliferation, and apoptosis in non-APL AML cells...
February 27, 2018: Cancer Research
Zhi-Jian Han, Yan-Hu Feng, Bao-Hong Gu, Yu-Min Li, Hao Chen
SUMOylation is a reversible post-translational modification which has emerged as a crucial molecular regulatory mechanism, involved in the regulation of DNA damage repair, immune responses, carcinogenesis, cell cycle progression and apoptosis. Four SUMO isoforms have been identified, which are SUMO1, SUMO2/3 and SUMO4. The small ubiquitin-like modifier (SUMO) pathway is conserved in all eukaryotes and plays pivotal roles in the regulation of gene expression, cellular signaling and the maintenance of genomic integrity...
February 22, 2018: International Journal of Oncology
Nigus Ambaye, Chih-Hong Chen, Swati Khanna, Yi-Jia Li, Yuan Chen
Streptonigrin (CAS no. 3930-19-6) is a natural product shown to have anti tumor activities in clinical trials conducted in the 1960s-1970s. However, its use in clinical studies eventually faded, and the molecular mechanisms of streptonigrin anti-tumor effects remain poorly defined. Despite the lack of its current clinical use, efforts on its total synthesis have continued. Here, we show that streptonigrin binds and inhibits the SUMO-specific protease SENP1. NMR studies identified that streptonigrin binds to SENP1 on the surface where SUMO binds and disrupts SENP1-SUMO1 interaction...
February 26, 2018: Biochemistry
Paula Ana Iribarren, Lucía Ayelén Di Marzio, María Agustina Berazategui, Javier Gerardo De Gaudenzi, Vanina Eder Alvarez
SUMOylation is a post-translational modification conserved in eukaryotic organisms that involves the covalent attachment of the small ubiquitin-like protein SUMO to internal lysine residues in target proteins. This tag usually alters the interaction surface of the modified protein and can be translated into changes in its biological activity, stability or subcellular localization, among other possible outputs. SUMO can be attached as a single moiety or as SUMO polymers in case there are internal acceptor sites in SUMO itself...
2018: PloS One
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