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Shan-Ling Liu, Feng-Hou Gao
Small ubiquitin-like modifier (SUMOylation) is a reversible post-translational modification, which plays important roles in numerous biological processes. SUMO could be covalently attached to target proteins in an isopeptide bond manner that occurs via a lysine ε-amino group on the target proteins and the glycine on SUMO C-terminus. This covalent binding could affect the subcellular localization and stability of target proteins. SUMO modification can be reversed by members of the Sentrin/SUMO-specific proteases (SENPs) family, which are highly evolutionarily conserved from yeast to human...
June 13, 2018: Biochimie
Claudio Ponte de Albuquerque, Raymond T Suhandynata, Christopher R Carlson, Wei-Tsuang Yuan, Huilin Zhou
Ulp1 and Ulp2, in the yeast Saccharomyces cerevisiae, are the founding members of deSUMOylating enzymes. These enzymes remove Small Ubiquitin-like Modifier (SUMO) from proteins and are conserved in all eukaryotes. Previous studies have shown that Ulp1 deSUMOylates the bulk of intracellular SUMOylated proteins, while Ulp2 is a highly specific enzyme. However, the mechanism for Ulp2's substrate specificity has been insufficiently understood. Here we show that the C-terminal regulatory domain of Ulp2 contains three distinct, yet conserved, motifs that control its in vivo substrate specificity and cell growth...
June 14, 2018: Journal of Biological Chemistry
Swastika Sanyal, Lucia Molnarova, Judita Richterova, Barbora Huraiova, Zsigmond Benko, Silvia Polakova, Ingrid Cipakova, Andrea Sevcovicova, Katarina Gaplovska-Kysela, Karl Mechtler, Lubos Cipak, Juraj Gregan
The canonical role of cohesin is to mediate sister chromatid cohesion. In addition, cohesin plays important roles in processes such as DNA repair and regulation of gene expression. Mounting evidence suggests that various post-translational modifications including phosphorylation, acetylation and SUMOylation regulate cohesin functions. Our mass-spectrometry analysis of cohesin purified from Schizosaccharomyces pombe cells revealed that the cohesin subunit Psm1 is methylated on two evolutionarily conserved lysine residues K536 and K1200...
June 13, 2018: Journal of Cell Science
Reinhard Brunmeir, Feng Xu
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and they are essential regulators of cell differentiation, tissue development, and energy metabolism. Given their central roles in sensing the cellular metabolic state and controlling metabolic homeostasis, PPARs became important targets of drug development for the management of metabolic disorders. The function of PPARs is mainly regulated through ligand binding, which induces structural changes, further affecting the interactions with co-activators or co-repressors to stimulate or inhibit their functions...
June 12, 2018: International Journal of Molecular Sciences
Yi-Jia Li, Li Du, Grace Aldana-Masangkay, Xiuli Wang, Ryan Urak, Stephen J Forman, Steven T Rosen, Yuan Chen
The miR-34 family of microRNAs suppresses the expression of proteins involved in pluripotency and oncogenesis. miR-34 expression is frequently reduced in cancers; however, the regulation of their expression is not well understood. We used genome-wide miRNA profiling and mechanistic analysis to show that SUMOylation regulates miR-34b/c expression, which impacts the expression of c-Myc and other tested miR-34 targets. We used site-directed mutagenesis and other methods to show that protein kinase B (also known as Akt) phosphorylation of FOXO3a plays an important role in SUMOylation-dependent expression of miR-34b/c...
June 9, 2018: Nucleic Acids Research
Yan-Yun Liu, Gregory A Brent
Thyroid hormone has a broad range of biological effects, both during development and in the adult. Nuclear thyroid hormone action is mediated by thyroid hormone receptor (TR) α and β. Thyroid hormone also has nongenomic actions at the membrane, which are less well characterized. Both TRα and TRβ undergo posttranslational modification, including phosphorylation, acetylation, and recently identified sumoylation. These posttranslational modifications have been shown to influence thyroid hormone signaling by altering TR DNA binding, TR interaction with cofactors, and TR-mediated transcription...
2018: Methods in Molecular Biology
John T Crowl, Daniel B Stetson
Detection of nucleic acids by innate immune sensors triggers the production of type I interferons (IFNs). While IFNs are essential for host defense against viral infection, dysregulated production of IFNs underlies numerous autoinflammatory diseases. We have found that the loss of sumoylation results in a potent, spontaneous IFN response. Vertebrates possess three small ubiquitin-like modifiers (SUMOs) that can be conjugated onto target proteins and alter protein function in diverse but still poorly characterized ways...
June 11, 2018: Proceedings of the National Academy of Sciences of the United States of America
Zhiqing Yuan, Guiyang Wang, Junwen Qu, Xiaopeng Wang, Kewei Li
AIMS: Vitamin A and its metabolites has been found to be protective against cholestatic liver injury, but the exact underlying mechanisms involved in cholestatic liver injury remain unclear. The objective of this study was to determine the function and mechanisms of 9-cis-retinoic acid, the metabolite of vitamin A, in cholestatic liver injury. METHODS: The bile duct ligated (BDL) mice were treated with 9-cis-retinoic acid by intravenous injection through the tail for 10 days...
June 6, 2018: Biochemical and Biophysical Research Communications
Hana M Odeh, Etienne Coyaud, Brian Raught, Michael J Matunis
Sumoylation regulates a wide range of essential cellular functions, many of which are associated with activities in the nucleus. Although there is also emerging evidence for the involvement of SUMO at intracellular membranes, the mechanisms by which sumoylation is regulated at membranes is largely unexplored. In this study, we report that the SUMO-specific isopeptidase, SENP2, uniquely associates with intracellular membranes. Using in vivo analyses and in vitro binding assays, we show that SENP2 is targeted to intracellular membranes via a predicted N-terminal amphipathic α-helix that promotes direct membrane binding...
June 6, 2018: Molecular Biology of the Cell
Gabriel Heras, Arvind Venkat Namuduri, Leonardo Traini, Ganna Shevchenko, Alexander Falk, Sara Bergström Lind, Jia Mi, Geng Tian
The Muscle RING-finger protein-1 (MuRF1) is an E3 ubiquitin ligase expressed in skeletal and cardiac muscle tissues and it plays important roles in muscle remodeling. Upregulation of MuRF1 gene transcription participates in skeletal muscle atrophy, on contrary downregulation of protein expression leads to cardiac hypertrophy. MuRF1 gene point mutations have been found to generate protein aggregate myopathies (PAMs) defined as muscle disorder characterized by protein accumulation in muscle fibers. We have discovered that MuRF1 turned out to be also a target for a new post-translational modification arbitrated by conjugation of SUMO-1 and it is mediated by the SUMO ligases E2 UBC9 and the E3 PIASγ/4...
June 4, 2018: Journal of Molecular Cell Biology
Maxime Wc Rousseaux, Jean-Pierre Revelli, Gabriel E Vázquez-Vélez, Ji-Yoen Kim, Evelyn Craigen, Kristyn Gonzales, Jaclyn Beckinghausen, Huda Y Zoghbi
Alzheimer's and Parkinson's disease are late onset neurodegenerative diseases that will require therapy over decades to mitigate the effects of disease-driving proteins such tau and α-synuclein (α-Syn). Previously we found that TRIM28 regulates the levels and toxicity of α-Syn and tau (<xref ref-type="bibr" rid="bib21">Rousseaux et al., 2016</xref>). However, it was not clear how TRIM28 regulates α-Syn and it was not known if its chronic inhibition later in life was safe...
June 4, 2018: ELife
Takuma Maruyama, Yoichiro Abe, Takako Niikura
Amyloid β, a key molecule in the pathogenesis of Alzheimer's disease (AD), is produced from amyloid precursor protein (APP) by the cleavage of secretases. APP is SUMOylated near the cleavage site of β-secretase. SUMOylation of APP reduces amyloid β production, but its regulatory system is still unclear. SUMOylation, a modification at a lysine residue of a target protein, is mediated by activating, conjugating, and ligating enzymes and is reversed by a family of sentrin/SUMO-specific proteases (SENPs). Here, we found that both SENP1 and SENP2 induced de-SUMOylation of APP...
April 2018: Heliyon
Joohyun Ryu, Do Hee Lee
We previously reported that SUMOylation promotes the aggregation of ataxin-1 and JNK is involved in the process. Here we show that dual-specificity phosphatase 18 (DUSP18), a member of protein tyrosine phosphatases, exerts the opposite effects on ataxin-1. DUSP18 associated with ataxin-1 and suppressed JNK activated by ataxin-1. Interestingly DUSP18, but not the other DUSPs interacting with ataxin-1, caused the mobility shift of ataxin-1. De-phosphorylation by DUSP18 was initially suspected as a cause for such an effect; however, the phosphorylation of ataxin-1 was unchanged...
May 28, 2018: Biochemical and Biophysical Research Communications
Jennifer Alagu, Yoko Itahana, Faizal Sim, Sheng-Hao Chao, Xuezhi Bi, Koji Itahana
The ability of cells to induce the appropriate transcriptional response to inflammatory stimuli is crucial for the timely induction of host defense mechanisms. Although a role for tumor suppressor p14ARF (ARF) in the innate immune response was previously demonstrated, the underlying mechanism is still unclear. ARF is a potent upregulator of protein SUMOylation; however, no association of this function with the immune system has been made. In this study, we show the unique role of ARF in IFN-γ-induced immune response using human cell lines...
May 30, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Liberty François-Moutal, Erik T Dustrude, Yue Wang, Tatiana Brustovetsky, Angie Dorame, Weina Ju, Aubin Moutal, Samantha Perez-Miller, Nickolay Brustovetsky, Vijay Gokhale, May Khanna, Rajesh Khanna
We previously reported that destruction of the small ubiquitin-like modifier (SUMO) modification site in the axonal collapsin response mediator protein 2 (CRMP2) was sufficient to selectively decrease trafficking of the voltage-gated sodium channel NaV1.7 and reverse neuropathic pain. Here, we further interrogate the biophysical nature of the interaction between CRMP2 and the SUMOylation machiner affinity between CRMP2 and Ubc9. A heptamer peptide harboring CRMP2's SUMO motif, also bound with similar affinity to Ubc9 and disrupted the CRMP2-Ubc9 interaction in a concentration-dependent manner...
May 25, 2018: Pain
Konstantin Tomanov, Ella Nukarinen, Jorge Vicente, Guillermina M Mendiondo, Nikola Winter, Lilian Nehlin, Wolfram Weckwerth, Michael J Holdsworth, Markus Teige, Andreas Bachmair
Post-translational modifications are essential mediators between stimuli from development or the environment and adaptive transcriptional patterns. Recent data allow a first glimpse at how two modifications, phosphorylation and sumoylation, act interdependently to modulate stress responses. In particular, many components of the SUMO conjugation system are phosphoproteins, and some regulators and enzymes of protein phosphorylation can be sumoylated. Equally important, however, a number of proteins can be subject to both modifications...
May 25, 2018: Journal of Experimental Botany
Andrea Flores Burroughs, Sylvia Eluhu, Diva Whalen, J Shawn Goodwin, Amos M Sakwe, Ifeanyi J Arinze
BACKGROUND/AIMS: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine-zipper transcription factor essential for cellular responses to oxidative stress. Degradation of Nrf2 in the cytoplasm, mediated by Keap1-Cullin3/RING box1 (Cul3-Rbx1) E3 ubiquitin ligase and the proteasome, is considered the primary pathway controlling the cellular abundance of Nrf2. Although the nucleus has been implicated in the degradation of Nrf2, little information is available on how this compartment participates in degrading Nrf2...
May 22, 2018: Cellular Physiology and Biochemistry
Henrick Horita, Andy Law, Kim Middleton
Post-translational modification (PTM) crosstalk is recognized as a major cell-regulatory mechanism, and studies of several proteins have validated the premise that PTMs work in concert. Previous work by our group investigated the potential PTM crosstalk on proteins in the EGFR-Ras-c-Fos axis by utilizing a comprehensive set of PTM reagents termed Signal-Seeker toolkits. In this study, these tools were used to investigate the potential PTM crosstalk that occurs in acetylated mitochondrial proteins in response to a mitochondrial stress-inducing agent hydrogen peroxide (H₂O₂)...
May 22, 2018: Proteomes
Yanfang Yang, Zijing Xia, Xixi Wang, Xinyu Zhao, Zenghua Sheng, Yang Ye, Gu He, Liangxue Zhou, Hongxia Zhu, Ningzhi Xu, Shufang Liang
SUMOylation, one of post-translational modifications, is covalently modified on lysine residues of a target protein through an enzymatic cascade reaction similar to protein ubiquitination. Along with identification of many SUMOylated proteins, protein SUMOylation has been proven to regulate multiple biological activities including transcription, cell cycle, DNA repair and innate immunity. The dysregulation of protein SUMOylation and deSUMOylation modification is linked with carcinogenesis and tumor progression...
May 21, 2018: Molecular Pharmacology
Maria Lauda Tomasi, Komal Ramani
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. The large spectrum of protein post-translational modification (PTM) includes numerous critical signaling events that occur during neoplastic transformation. PTMs occur to nearly all proteins and increase the functional diversity of proteins. We have reviewed the role of two major PTMs, SUMOylation and phosphorylation, in the altered signaling of key players in HCC...
2018: Translational Gastroenterology and Hepatology
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