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Frontiers in Cellular and Infection... 2021Malaria is a parasitic disease that represents a public health problem worldwide. Protozoans of the genus are responsible for causing malaria in humans. species have a... (Review)
Review
Malaria is a parasitic disease that represents a public health problem worldwide. Protozoans of the genus are responsible for causing malaria in humans. species have a complex life cycle that requires post-translational modifications (PTMs) to control cellular activities temporally and spatially and regulate the levels of critical proteins and cellular mechanisms for maintaining an efficient infection and immune evasion. SUMOylation is a PTM formed by the covalent linkage of a small ubiquitin-like modifier protein to the lysine residues on the protein substrate. This PTM is reversible and is triggered by the sequential action of three enzymes: E1-activating, E2-conjugating, and E3 ligase. On the other end, ubiquitin-like-protein-specific proteases in yeast and sentrin-specific proteases in mammals are responsible for processing SUMO peptides and for deconjugating SUMOylated moieties. Further studies are necessary to comprehend the molecular mechanisms and cellular functions of SUMO in . The emergence of drug-resistant malaria parasites prompts the discovery of new targets and antimalarial drugs with novel mechanisms of action. In this scenario, the conserved biological processes regulated by SUMOylation in the malaria parasites such as gene expression regulation, oxidative stress response, ubiquitylation, and proteasome pathways, suggest SUMO as a new potential drug target. This mini-review focuses on the current understanding of the mechanism of action of the SUMO during the coordinated multi-step life cycle of and discusses them as attractive new target proteins for the development of parasite-specific inhibitors and therapeutic intervention toward malaria disease.
Topics: Animals; Antimalarials; Humans; Malaria; Plasmodium; Plasmodium falciparum; Sumoylation
PubMed: 34178724
DOI: 10.3389/fcimb.2021.685866 -
Viruses Aug 2015Posttranslational modifications (PTMs) of proteins include enzymatic changes by covalent addition of cellular regulatory determinants such as ubiquitin (Ub) and small... (Review)
Review
Posttranslational modifications (PTMs) of proteins include enzymatic changes by covalent addition of cellular regulatory determinants such as ubiquitin (Ub) and small ubiquitin-like modifier (SUMO) moieties. These modifications are widely used by eukaryotic cells to control the functional repertoire of proteins. Over the last decade, it became apparent that the repertoire of ubiquitiylation and SUMOylation regulating various biological functions is not restricted to eukaryotic cells, but is also a feature of human virus families, used to extensively exploit complex host-cell networks and homeostasis. Intriguingly, besides binding to host SUMO/Ub control proteins and interfering with the respective enzymatic cascade, many viral proteins mimic key regulatory factors to usurp this host machinery and promote efficient viral outcomes. Advanced detection methods and functional studies of ubiquitiylation and SUMOylation during virus-host interplay have revealed that human viruses have evolved a large arsenal of strategies to exploit these specific PTM processes. In this review, we highlight the known viral analogs orchestrating ubiquitin and SUMO conjugation events to subvert and utilize basic enzymatic pathways.
Topics: Host-Pathogen Interactions; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Ubiquitin; Ubiquitination; Viruses
PubMed: 26343706
DOI: 10.3390/v7092849 -
International Journal of Molecular... May 2021Small ubiquitin-like modifier (SUMO)-targeted E3 ubiquitin ligases (STUbLs) are specialized enzymes that recognize SUMOylated proteins and attach ubiquitin to them. They... (Review)
Review
Small ubiquitin-like modifier (SUMO)-targeted E3 ubiquitin ligases (STUbLs) are specialized enzymes that recognize SUMOylated proteins and attach ubiquitin to them. They therefore connect the cellular SUMOylation and ubiquitination circuits. STUbLs participate in diverse molecular processes that span cell cycle regulated events, including DNA repair, replication, mitosis, and transcription. They operate during unperturbed conditions and in response to challenges, such as genotoxic stress. These E3 ubiquitin ligases modify their target substrates by catalyzing ubiquitin chains that form different linkages, resulting in proteolytic or non-proteolytic outcomes. Often, STUbLs function in compartmentalized environments, such as the nuclear envelope or kinetochore, and actively aid in nuclear relocalization of damaged DNA and stalled replication forks to promote DNA repair or fork restart. Furthermore, STUbLs reside in the same vicinity as SUMO proteases and deubiquitinases (DUBs), providing spatiotemporal control of their targets. In this review, we focus on the molecular mechanisms by which STUbLs help to maintain genome stability across different species.
Topics: Animals; DNA Repair; Genomic Instability; Humans; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 34065507
DOI: 10.3390/ijms22105391 -
PloS One 2011Human early growth response-1 (EGR1) is a member of the zing-finger family of transcription factors induced by a range of molecular and environmental stimuli including...
BACKGROUND
Human early growth response-1 (EGR1) is a member of the zing-finger family of transcription factors induced by a range of molecular and environmental stimuli including epidermal growth factor (EGF). In a recently published paper we demonstrated that integrin/EGFR cross-talk was required for Egr1 expression through activation of the Erk1/2 and PI3K/Akt/Forkhead pathways. EGR1 activity and stability can be influenced by many different post-translational modifications such as acetylation, phosphorylation, ubiquitination and the recently discovered sumoylation. The aim of this work was to assess the influence of sumoylation on EGF induced Egr1 expression and/or stability.
METHODS
We modulated the expression of proteins involved in the sumoylation process in ECV304 cells by transient transfection and evaluated Egr1 expression in response to EGF treatment at mRNA and protein levels.
RESULTS
We demonstrated that in ECV304 cells Egr1 was transiently induced upon EGF treatment and a fraction of the endogenous protein was sumoylated. Moreover, SUMO-1/Ubc9 over-expression stabilized EGF induced ERK1/2 phosphorylation and increased Egr1 gene transcription. Conversely, in SUMO-1/Ubc9 transfected cells, EGR1 protein levels were strongly reduced. Data obtained from protein expression and ubiquitination analysis, in the presence of the proteasome inhibitor MG132, suggested that upon EGF stimuli EGR1 sumoylation enhanced its turnover, increasing ubiquitination and proteasome mediated degradation.
CONCLUSIONS
Here we demonstrate that SUMO-1 modification improving EGR1 ubiquitination is involved in the modulation of its stability upon EGF mediated induction.
Topics: Cell Line; Early Growth Response Protein 1; Enzyme Activation; Epidermal Growth Factor; Gene Expression Regulation; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Proteasome Endopeptidase Complex; Protein Stability; Proteolysis; SUMO-1 Protein; Sumoylation; Time Factors; Transcription, Genetic; Ubiquitin-Conjugating Enzymes
PubMed: 21998680
DOI: 10.1371/journal.pone.0025676 -
Molecular Cell Mar 2013Ubiquitylation and sumoylation, the covalent attachment of the polypeptides ubiquitin and SUMO, respectively, to target proteins, are pervasive mechanisms for... (Review)
Review
Ubiquitylation and sumoylation, the covalent attachment of the polypeptides ubiquitin and SUMO, respectively, to target proteins, are pervasive mechanisms for controlling cellular functions. Here, we summarize the key steps and enzymes involved in ubiquitin and SUMO conjugation and provide an overview of how they are crucial for maintaining genome stability. Specifically, we review research that has revealed how ubiquitylation and sumoylation regulate and coordinate various pathways of DNA damage recognition, signaling, and repair at the biochemical, cellular, and whole-organism levels. In addition to providing key insights into the control and importance of DNA repair and associated processes, such work has established paradigms for regulatory control that are likely to extend to other cellular processes and that may provide opportunities for better understanding and treatment of human disease.
Topics: Animals; DNA Damage; DNA Repair; Genomic Instability; Humans; SUMO-1 Protein; Signal Transduction; Sumoylation; Ubiquitin
PubMed: 23416108
DOI: 10.1016/j.molcel.2013.01.017 -
Endocrinology Feb 2017Posttranslational modifications (PTMs) occur to nearly all proteins, are catalyzed by specific enzymes, and are subjected to tight regulation. They have been shown to be... (Review)
Review
Posttranslational modifications (PTMs) occur to nearly all proteins, are catalyzed by specific enzymes, and are subjected to tight regulation. They have been shown to be a powerful means by which the function of proteins can be modified, resulting in diverse effects. Technological advances such as the increased sensitivity of mass spectrometry-based techniques and availability of mutant animal models have enhanced our understanding of the complexities of their regulation and the effect they have on protein function. However, the role that PTMs have in a pathological context still remains unknown for the most part. PTMs enable the modulation of nuclear receptor function in a rapid and reversible manner in response to varied stimuli, thereby dramatically altering their activity in some cases. This review focuses on acetylation, phosphorylation, SUMOylation, and O-GlcNAcylation, which are the 4 most studied PTMs affecting lipid-regulated nuclear receptor biology, as well as on the implications of such modifications on metabolic pathways under homeostatic and pathological situations. Moreover, we review recent studies on the modulation of PTMs as therapeutic targets for metabolic diseases.
Topics: Acetylation; Animals; Humans; Lipid Metabolism; Phosphorylation; Protein Processing, Post-Translational; Receptors, Cytoplasmic and Nuclear; Sumoylation
PubMed: 27925773
DOI: 10.1210/en.2016-1577 -
International Journal of Molecular... Oct 2022SUMOylation is a reversible post-translational modification (PTM) involving covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate...
SUMOylation is a reversible post-translational modification (PTM) involving covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. Dysregulation of SUMOylation and deSUMOylation results in cellular malfunction and is linked to various diseases, such as cancer. Sentrin-specific proteases (SENPs) were identified for the maturation of SUMOs and the deconjugation of SUMOs from their substrate proteins. Hence, this is a promising target tackling the dysregulation of the SUMOylation process. Herein, we report the discovery of a novel protein-protein interaction (PPI) inhibitor for SENP1-SUMO1 by virtual screening and subsequent medicinal chemistry optimization of the hit molecule. The optimized inhibitor ZHAWOC8697 showed IC values of 8.6 μM against SENP1 and 2.3 μM against SENP2. With a photo affinity probe the SENP target was validated. This novel SENP inhibitor represents a new valuable tool for the study of SUMOylation processes and the SENP-associated development of small molecule-based treatment options.
Topics: Small Ubiquitin-Related Modifier Proteins; Sumoylation; Pyruvates; Endopeptidases; Peptide Hydrolases
PubMed: 36292935
DOI: 10.3390/ijms232012085 -
The New Phytologist Mar 2023Pathogenic fungi are subject to DNA damage stress derived from host immune responses during infection. Small ubiquitin-like modifier (SUMO) modification and precursor...
Pathogenic fungi are subject to DNA damage stress derived from host immune responses during infection. Small ubiquitin-like modifier (SUMO) modification and precursor (pre)-mRNA splicing are both involved in DNA damage response (DDR). However, the mechanisms of how SUMOylation and splicing coordinated in DDR remain largely unknown. Combining with biochemical analysis, RNA-Seq method, and biological analysis, we report that SUMO pathway participates in DDR and virulence in Fusarium graminearum, a causal agent of Fusarium head blight of cereal crops world-wide. Interestingly, a key transcription factor FgSR is SUMOylated upon DNA damage stress. SUMOylation regulates FgSR nuclear-cytoplasmic partitioning and its phosphorylation by FgMec1, and promotes its interaction with chromatin remodeling complex SWI/SNF for activating the expression of DDR-related genes. Moreover, the SWI/SNF complex was found to further recruit splicing-related NineTeen Complex, subsequently modulates pre-mRNA splicing during DDR. Our findings reveal a novel function of SUMOylation in DDR by regulating a transcription factor to orchestrate gene expression and pre-mRNA splicing to overcome DNA damage during the infection of F. graminearum, which advances the understanding of the delicate regulation of DDR by SUMOylation in pathogenic fungi, and extends the knowledge of cooperation of SUMOylation and pre-mRNA splicing in DDR in eukaryotes.
Topics: Sumoylation; RNA Precursors; Small Ubiquitin-Related Modifier Proteins; Transcription Factors; DNA Damage
PubMed: 36539920
DOI: 10.1111/nph.18692 -
RSRC1 SUMOylation enhances SUMOylation and inhibits transcriptional activity of estrogen receptor β.FEBS Letters Jun 2015The transcription factor estrogen receptor β (ERβ) plays roles in the central nervous, endocrine, cardiovascular, and immune systems. ERβ can be SUMOylated. However,...
The transcription factor estrogen receptor β (ERβ) plays roles in the central nervous, endocrine, cardiovascular, and immune systems. ERβ can be SUMOylated. However, the underlying mechanism remains unclear. Here, we show that RSRC1/SRrp53 interacts with ERβ and SUMOylation of RSRC1 is required for regulation of PIAS1-mediated ERβ SUMOylation. RSRC1 promotes ERβ SUMOylation through enhanced interaction between ERβ and PIAS1. RSRC1 represses ERβ transcriptional activity through regulation of ERβ SUMOylation. By establishing RSRC1 as a novel cofactor for SUMOylation, our data provide insight into regulation of ERβ SUMOylation and indicate that SUMOylation of one protein can regulate another protein SUMOylation.
Topics: Cell Line, Tumor; Estrogen Receptor beta; HEK293 Cells; Humans; Immunoblotting; Nuclear Proteins; Protein Binding; Protein Inhibitors of Activated STAT; Protein Interaction Mapping; Sumoylation; Transcription, Genetic; Two-Hybrid System Techniques
PubMed: 25937118
DOI: 10.1016/j.febslet.2015.04.035 -
Viruses Mar 2021SUMOylation is a highly dynamic ubiquitin-like post-translational modification that is essential for cells to respond to and resolve various genotoxic and proteotoxic... (Review)
Review
SUMOylation is a highly dynamic ubiquitin-like post-translational modification that is essential for cells to respond to and resolve various genotoxic and proteotoxic stresses. Virus infections also constitute a considerable stress scenario for cells, and recent research has started to uncover the diverse roles of SUMOylation in regulating virus replication, not least by impacting antiviral defenses. Here, we review some of the key findings of this virus-host interplay, and discuss the increasingly important contribution that large-scale, unbiased, proteomic methodologies are making to discoveries in this field. We highlight the latest proteomic technologies that have been specifically developed to understand SUMOylation dynamics in response to cellular stresses, and comment on how these techniques might be best applied to dissect the biology of SUMOylation during innate immunity. Furthermore, we showcase a selection of studies that have already used SUMO proteomics to reveal novel aspects of host innate defense against viruses, such as functional cross-talk between SUMO proteins and other ubiquitin-like modifiers, viral antagonism of SUMO-modified antiviral restriction factors, and an infection-triggered SUMO-switch that releases endogenous retroelement RNAs to stimulate antiviral interferon responses. Future research in this area has the potential to provide new and diverse mechanistic insights into host immune defenses.
Topics: Host Microbial Interactions; Humans; Immunity, Innate; Proteomics; Sumoylation; Virus Diseases; Virus Replication
PubMed: 33806893
DOI: 10.3390/v13030528