scholarly journals SUMO: From Bench to Bedside

2020 ◽  
Vol 100 (4) ◽  
pp. 1599-1619 ◽  
Author(s):  
Hui-Ming Chang ◽  
Edward T. H. Yeh
Keyword(s):  
Cellular Localization ◽  
Protein Modification ◽  
Redox Regulation ◽  
Biological Processes ◽  
Protein Activity ◽  
Protein Protein Interaction ◽  
The Family ◽  
Lysine Residues ◽  
Sumo Pathway ◽  
Posttranslational Protein Modification

Sentrin/small ubiquitin-like modifier (SUMO) is protein modification pathway that regulates multiple biological processes, including cell division, DNA replication/repair, signal transduction, and cellular metabolism. In this review, we will focus on recent advances in the mechanisms of disease pathogenesis, such as cancer, diabetes, seizure, and heart failure, which have been linked to the SUMO pathway. SUMO is conjugated to lysine residues in target proteins through an isopeptide linkage catalyzed by SUMO-specific activating (E1), conjugating (E2), and ligating (E3) enzymes. In steady state, the quantity of SUMO-modified substrates is usually a small fraction of unmodified substrates due to the deconjugation activity of the family Sentrin/SUMO-specific proteases (SENPs). In contrast to the complexity of the ubiquitination/deubiquitination machinery, the biochemistry of SUMOylation and de-SUMOylation is relatively modest. Specificity of the SUMO pathway is achieved through redox regulation, acetylation, phosphorylation, or other posttranslational protein modification of the SUMOylation and de-SUMOylation enzymes. There are three major SUMOs. SUMO-1 usually modifies a substrate as a monomer; however, SUMO-2/3 can form poly-SUMO chains. The monomeric SUMO-1 or poly-SUMO chains can interact with other proteins through SUMO-interactive motif (SIM). Thus SUMO modification provides a platform to enhance protein-protein interaction. The consequence of SUMOylation includes changes in cellular localization, protein activity, or protein stability. Furthermore, SUMO may join force with ubiquitin to degrade proteins through SUMO-targeted ubiquitin ligases (STUbL). After 20 yr of research, SUMO has been shown to play critical roles in most, if not all, biological pathways. Thus the SUMO enzymes could be targets for drug development to treat human diseases.

scholarly journals Quantitative proteomics reveals extensive lysine ubiquitination in the Arabidopsis root proteome and uncovers novel transcription factor stability states

2021 ◽  
Author(s):  
Gaoyuan Song ◽  
Damilola Olatunji ◽  
Christian Montes ◽  
Natalie M Clark ◽  
Yunting Pu ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Site Directed Mutagenesis ◽  
Biological Processes ◽  
Protein Activity ◽  
Helix Loop Helix ◽  
Primary Roots ◽  
Lysine Residues ◽  
Ubiquitin Proteasome ◽  
The Stability

Protein activity, abundance, and stability can be regulated by posttranslational modification including ubiquitination. Ubiquitination is conserved among eukaryotes and plays a central role in modulating cellular function and yet we lack comprehensive catalogs of proteins that are modified by ubiquitin in plants. In this study, we describe an antibody-based approach to enrich peptides containing the di-glycine (diGly) remnant of ubiquitin and coupled that with isobaric labeling to enable quantification, from up to 16-multiplexed samples, for plant tissues. Collectively, we identified 7,130 diGly-modified lysine residues sites arising from 3,178 proteins in Arabidopsis primary roots. These data include ubiquitin proteasome dependent ubiquitination events as well as ubiquitination events associated with auxin treatment. Gene Ontology analysis indicated that ubiquitinated proteins are associated with numerous biological processes including hormone signaling, plant defense, protein homeostasis, and root morphogenesis. We determined the ubiquitinated lysine residues that directly regulate the stability of the transcription factors CRYPTOCHROME-INTERACTING BASIC-HELIX-LOOP-HELIX 1 (CIB1), CIB1 LIKE PROTEIN 2 (CIL2), and SENSITIVE TO PROTON RHIZOTOXICITY (STOP1) using site directed mutagenesis and in vivo degradation assays. These comprehensive site-level ubiquitinome profiles provide a wealth of data for future studies related to modulation of biological processes mediated by this posttranslational modification in plants.

scholarly journals Age-Associated Changes in Antioxidants and Redox Proteins of Rat Heart

2019 ◽  
pp. 883-892
Author(s):  
P. Kaplán ◽  
Z. Tatarková ◽  
L. Lichardusová ◽  
M. Kmeťová Sivoňová ◽  
A. Tomašcová ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Protein Modification ◽  
Redox Regulation ◽  
Thioredoxin Reductase ◽  
Redox Balance ◽  
Regulatory Systems ◽  
Age Related ◽  
Uniform Array ◽  
Old Rats ◽  
Posttranslational Protein Modification

Oxidative stress and decline in cellular redox regulation have been hypothesized to play a key role in cardiovascular aging; however, data on antioxidant and redox regulating systems in the aging heart are controversial. The aim of the present study was to examine the effect of aging on critical antioxidant enzymes and two major redox-regulatory systems glutathione (GSH) and thioredoxin (Trx) system in hearts from adult (6-month-old), old (15-month-old), and senescent (26-month-old) rats. Aging was associated with a non-uniform array of changes, including decline in contents of reduced GSH and total mercaptans in the senescent heart. The activities of Mn-superoxide dismutase (SOD2), glutathione peroxidase (GPx), glutathione reductase (GR), and thioredoxin reductase (TrxR) exhibited an age-related decline, whereas catalase was unchanged and Cu,Zn-superoxide dismutase (SOD1) displayed only slight decrease in old heart and was unchanged in the senescent heart. GR, Trx, and peroxiredoxin levels were significantly reduced in old and/or senescent hearts, indicating a diminished expression of these proteins. In contrast, SOD2 level was unchanged in the old heart and was slightly elevated in the senescent heart. Decline in GPx activity was accompanied by a loss of GPx level only in old rats, the level in senescent heart was unchanged. These results indicate age-related posttranslational protein modification of SOD2 and GPx. In summary, our data suggest that changes are more pronounced in senescent than in old rat hearts and support the view that aging is associated with disturbed redox balance that could alter cellular signaling and regulation.

scholarly journals Characterization of NO-Induced Nitrosative Status in Human Placenta from Pregnant Women with Gestational Diabetes Mellitus

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Francisco Visiedo ◽  
Celeste Santos-Rosendo ◽  
Rosa M. Mateos-Bernal ◽  
M. del Mar Gil-Sánchez ◽  
Fernando Bugatto ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Protein Modification ◽  
Placental Tissue ◽  
No Production ◽  
Protein Activity ◽  
Cellular Signal ◽  
Posttranslational Protein Modification ◽  
Biotin Switch

Dysregulation of NO production is implicated in pregnancy-related diseases, including gestational diabetes mellitus (GDM). The role of NO and its placental targets in GDM pregnancies has yet to be determined. S-Nitrosylation is the NO-derived posttranslational protein modification that can modulate biological functions by forming NO-derived complexes with longer half-life, termed S-nitrosothiol (SNO). Our aim was to examine the presence of endogenous S-nitrosylated proteins in cysteine residues in relation to antioxidant defense, apoptosis, and cellular signal transduction in placental tissue from control (n=8) and GDM (n=8) pregnancies. S-Nitrosylation was measured using the biotin-switch assay, while the expression and protein activity were assessed by immunoblotting and colorimetric methods, respectively. Results indicated that catalase and peroxiredoxin nitrosylation levels were greater in GDM placentas, and that was accompanied by reduced catalase activity. S-Nitrosylation of ERK1/2 and AKT was increased in GDM placentas, and their activities were inhibited. Activities of caspase-3 and caspase-9 were increased, with the latter also showing diminished nitrosylation levels. These findings suggest that S-nitrosylation is a little-known, but critical, mechanism by which NO directly modulates key placental proteins in women with GDM and, as a consequence, maternal and fetal anomalies during pregnancy can occur.

scholarly journals Acetylation of conserved DVL-1 lysines regulates its nuclear translocation and binding to gene promoters in triple-negative breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Monica Sharma ◽  
Deborah Molehin ◽  
Isabel Castro-Piedras ◽  
Edgar G. Martinez ◽  
Kevin Pruitt
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Translational Regulation ◽  
Cellular Localization ◽  
Triple Negative ◽  
Nuclear Translocation ◽  
Gene Promoters ◽  
Post Translational Modification ◽  
Protein Activity ◽  
Lysine Residues

Abstract Dishevelled (DVL) proteins are central mediators of the Wnt signalling pathway and are versatile regulators of several cellular processes, yet little is known about their post-translational regulation. Acetylation is a reversible post-translational modification (PTM) which regulates the function of several non-histone proteins involved in tumorigenesis. Since we previously demonstrated that lysine deacetylase, SIRT-1, regulates DVL protein levels and its function, we reasoned that DVL could potentially be a substrate for SIRT-1 mediated deacetylation. To further examine the potential role of multiple families of lysine deacetylases in the post-translational regulation of DVL, we screened for novel acetylation sites using liquid chromatography mass-spectrometry (LC-MS/MS) analysis. Herein, we report 12 DVL-1 lysine residues that show differential acetylation in response to changes in oxygen tension and deacetylase inhibition in triple-negative breast cancer (TNBC). PTMs are well documented to influence protein activity, and cellular localization. We also identify that acetylation of two key lysine residues, K69 and K285, present on the DIX and PDZ domains respectively, promote nuclear over cytoplasmic localization of DVL-1, and influences its promoter binding and regulation of genes implicated in cancer. Collectively, these findings for the first time, uncover acetylation as a novel layer of regulation of DVL-1 proteins.

scholarly journals HOX Protein Activity Regulation by Cellular Localization

2021 ◽  
Vol 9 (4) ◽  
pp. 56
Author(s):  
Laure Bridoux ◽  
Françoise Gofflot ◽  
René Rezsohazy
Keyword(s):  
Cellular Localization ◽  
Hox Genes ◽  
Model Organisms ◽  
Post Translational Modification ◽  
Protein Activity ◽  
Hox Proteins ◽  
Protein Protein Interaction ◽  
A Cell ◽  
Cell Type Specific ◽  
Hox Protein

While the functions of HOX genes have been and remain extensively studied in distinct model organisms from flies to mice, the molecular biology of HOX proteins remains poorly documented. In particular, the mechanisms involved in regulating the activity of HOX proteins have been poorly investigated. Nonetheless, based on data available from other well-characterized transcription factors, it can be assumed that HOX protein activity must be finely tuned in a cell-type-specific manner and in response to defined environmental cues. Indeed, records in protein–protein interaction databases or entries in post-translational modification registries clearly support that HOX proteins are the targets of multiple layers of regulation at the protein level. In this context, we review here what has been reported and what can be inferred about how the activities of HOX proteins are regulated by their intracellular distribution.

Review of Progress in Predicting Protein Methylation Sites

2019 ◽  
Vol 23 (15) ◽  
pp. 1663-1670 ◽  
Author(s):  
Chunyan Ao ◽  
Shunshan Jin ◽  
Yuan Lin ◽  
Quan Zou
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Transcriptional Activity ◽  
Regulation Of Gene Expression ◽  
Protein Methylation ◽  
Biological Processes ◽  
Post Translational Modification ◽  
Regulatory Enzymes ◽  
Lysine Residues ◽  
Arginine Residues

Protein methylation is an important and reversible post-translational modification that regulates many biological processes in cells. It occurs mainly on lysine and arginine residues and involves many important biological processes, including transcriptional activity, signal transduction, and the regulation of gene expression. Protein methylation and its regulatory enzymes are related to a variety of human diseases, so improved identification of methylation sites is useful for designing drugs for a variety of related diseases. In this review, we systematically summarize and analyze the tools used for the prediction of protein methylation sites on arginine and lysine residues over the last decade.

scholarly journals In vivo interactome profiling by enzyme‐catalyzed proximity labeling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yangfan Xu ◽  
Xianqun Fan ◽  
Yang Hu
Keyword(s):  
State Of The Art ◽  
Catalytic Efficiency ◽  
Biological Processes ◽  
Protein Protein Interaction ◽  
Current State ◽  
Protein Interactome ◽  
Potential Applications ◽  
Protein Protein Interaction Networks ◽  
Temporal And Spatial

AbstractEnzyme-catalyzed proximity labeling (PL) combined with mass spectrometry (MS) has emerged as a revolutionary approach to reveal the protein-protein interaction networks, dissect complex biological processes, and characterize the subcellular proteome in a more physiological setting than before. The enzymatic tags are being upgraded to improve temporal and spatial resolution and obtain faster catalytic dynamics and higher catalytic efficiency. In vivo application of PL integrated with other state of the art techniques has recently been adapted in live animals and plants, allowing questions to be addressed that were previously inaccessible. It is timely to summarize the current state of PL-dependent interactome studies and their potential applications. We will focus on in vivo uses of newer versions of PL and highlight critical considerations for successful in vivo PL experiments that will provide novel insights into the protein interactome in the context of human diseases.

scholarly journals PIAS1 potentiates the anti-EBV activity of SAMHD1 through SUMOylation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Farjana Saiada ◽  
Kun Zhang ◽  
Renfeng Li
Keyword(s):  
Lytic Replication ◽  
Dependent Manner ◽  
Dna Viruses ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Barr Virus ◽  
Sumo Ligase ◽  
Lysine Residues ◽  
Epstein Barr ◽  
Rna And Dna

Abstract Background Sterile alpha motif and HD domain 1 (SAMHD1) is a deoxynucleotide triphosphohydrolase (dNTPase) that restricts the infection of a variety of RNA and DNA viruses, including herpesviruses. The anti-viral function of SAMHD1 is associated with its dNTPase activity, which is regulated by several post-translational modifications, including phosphorylation, acetylation and ubiquitination. Our recent studies also demonstrated that the E3 SUMO ligase PIAS1 functions as an Epstein-Barr virus (EBV) restriction factor. However, whether SAMHD1 is regulated by PIAS1 to restrict EBV replication remains unknown. Results In this study, we showed that PIAS1 interacts with SAMHD1 and promotes its SUMOylation. We identified three lysine residues (K469, K595 and K622) located on the surface of SAMHD1 as the major SUMOylation sites. We demonstrated that phosphorylated SAMHD1 can be SUMOylated by PIAS1 and SUMOylated SAMHD1 can also be phosphorylated by viral protein kinases. We showed that SUMOylation-deficient SAMHD1 loses its anti-EBV activity. Furthermore, we demonstrated that SAMHD1 is associated with EBV genome in a PIAS1-dependent manner. Conclusion Our study reveals that PIAS1 synergizes with SAMHD1 to inhibit EBV lytic replication through protein–protein interaction and SUMOylation.

scholarly journals Identification of Key Candidate Genes Involved in the Progression of Idiopathic Pulmonary Fibrosis

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1123
Author(s):  
Yu Cui ◽  
Jie Ji ◽  
Jiwei Hou ◽  
Yi Tan ◽  
Xiaodong Han
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Candidate Genes ◽  
Expression Profiles ◽  
Biological Processes ◽  
Protein Protein Interaction ◽  
Novel Treatments ◽  
Kegg Pathway Analysis ◽  
Cell Components ◽  
Upregulated Genes

Idiopathic pulmonary fibrosis (IPF) is a lethal, agnogenic interstitial lung disease with limited therapeutic options. To investigate vital genes involved in the development of IPF, we integrated and compared four expression profiles (GSE110147, GSE53845, GSE24206, and GSE10667), including 87 IPF samples and 40 normal samples. By reanalyzing these datasets, we managed to identify 62 upregulated genes and 20 downregulated genes in IPF samples compared with normal samples. Differentially expressed genes (DEGs) were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to illustrate relevant pathways of IPF, biological processes, molecular function, and cell components. The DEGs were then subjected to protein–protein interaction (PPI) for network analysis, serving to find 11 key candidate genes (ANXA3, STX11, THBS2, MMP1, MMP9, MMP7, MMP10, SPP1, COL1A1, ITGB8, IGF1). The result of RT-qPCR and immunohistochemical staining verified our finding as well. In summary, we identified 11 key candidate genes related to the process of IPF, which may contribute to novel treatments of IPF.

scholarly journals Involvement of loop 5 lysine residues and the N-terminal β-hairpin of the ribotoxin hirsutellin A on its insecticidal activity

2016 ◽  
Vol 397 (2) ◽  
pp. 135-145 ◽  
Author(s):  
Miriam Olombrada ◽  
Lucía García-Ortega ◽  
Javier Lacadena ◽  
Mercedes Oñaderra ◽  
José G. Gavilanes ◽  
...  
Keyword(s):  
Active Sites ◽  
Structural Changes ◽  
The Other ◽  
Spatial Proximity ◽  
Ribonucleolytic Activity ◽  
The Family ◽  
Lysine Residues ◽  
Hirsutella Thompsonii ◽  
Close Spatial Proximity ◽  
High Degree

Abstract Ribotoxins are cytotoxic members of the family of fungal extracellular ribonucleases best represented by RNase T1. They share a high degree of sequence identity and a common structural fold, including the geometric arrangement of their active sites. However, ribotoxins are larger, with a well-defined N-terminal β-hairpin, and display longer and positively charged unstructured loops. These structural differences account for their cytotoxic properties. Unexpectedly, the discovery of hirsutellin A (HtA), a ribotoxin produced by the invertebrate pathogen Hirsutella thompsonii, showed how it was possible to accommodate these features into a shorter amino acid sequence. Examination of HtA N-terminal β-hairpin reveals differences in terms of length, charge, and spatial distribution. Consequently, four different HtA mutants were prepared and characterized. One of them was the result of deleting this hairpin [Δ(8-15)] while the other three affected single Lys residues in its close spatial proximity (K115E, K118E, and K123E). The results obtained support the general conclusion that HtA active site would show a high degree of plasticity, being able to accommodate electrostatic and structural changes not suitable for the other previously known larger ribotoxins, as the variants described here only presented small differences in terms of ribonucleolytic activity and cytotoxicity against cultured insect cells.

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