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Frontiers in Cellular and Infection... 2022SUMOylation is one of the post-translational modifications that have recently been described as a key regulator of various cellular, nuclear, metabolic, and...
SUMOylation is one of the post-translational modifications that have recently been described as a key regulator of various cellular, nuclear, metabolic, and immunological processes. The process of SUMOylation involves the modification of one or more lysine residues of target proteins by conjugation of a ubiquitin-like, small polypeptide known as SUMO for their degradation, stability, transcriptional regulation, cellular localization, and transport. Herein, for the first time, we report the involvement of the host SUMOylation pathway in the process of infection of , a causative agent of visceral leishmaniasis. Our data revealed that infection of to the host macrophages leads to upregulation of SUMOylation pathway genes and downregulation of a deSUMOylating gene, SENP1. Further, to confirm the effect of the host SUMOylation on the growth of , the genes associated with the SUMOylation pathway were silenced and parasite load was analyzed. The knockdown of the SUMOylation pathway led to a reduction in parasitic load, suggesting the role of the host SUMOylation pathway in the disease progression and parasite survival. Owing to the effect of the SUMOylation pathway in autophagy, we further investigated the status of host autophagy to gain mechanistic insights into how SUMOylation mediates the regulation of growth of . Knockdown of genes of host SUMOylation pathway led to the reduction of the expression levels of host autophagy markers while promoting autophagosome-lysosome fusion, suggesting SUMOylation-mediated autophagy in terms of autophagy initiation and autophagy maturation during parasite survival. The levels of reactive oxygen species (ROS) generation, nitric oxide (NO) production, and pro-inflammatory cytokines were also elevated upon the knockdown of genes of the host SUMOylation pathway during infection. This indicates the involvement of the SUMOylation pathway in the modulation of protective immune responses and thus favoring parasite survival. Taken together, the results of this study indicate the hijacking of the host SUMOylation pathway by toward the suppression of host immune responses and facilitation of host autophagy to potentially facilitate its survival. Targeting of SUMOylation pathway can provide a starting point for the design and development of novel therapeutic interventions to combat leishmaniasis.
Topics: Animals; Immunity; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Parasites; Sumoylation
PubMed: 35734580
DOI: 10.3389/fcimb.2022.878136 -
Biochemical and Biophysical Research... Jun 2017The meiotic G2/M1 transition is mostly regulated by posttranslational modifications, however, the cross-talk between different posttranslational modifications is not...
The meiotic G2/M1 transition is mostly regulated by posttranslational modifications, however, the cross-talk between different posttranslational modifications is not well-understood, especially in spermatocytes. Sumoylation has emerged as a critical regulatory event in several developmental processes, including reproduction. In mouse oocytes, inhibition of sumoylation caused various meiotic defects and led to aneuploidy. However, the role of sumoylation in male reproduction has only begun to be elucidated. Given the important role of several SUMO targets (including kinases) in meiosis, in this study, the role of sumoylation was addressed by monitoring the G2/M1 transition in pachytene spermatocytes in vitro upon inhibition of sumoylation. Furthermore, to better understand the cross-talk between sumoylation and phosphorylation, the activity of several kinases implicated in meiotic progression was also assessed upon down-regulation of sumoylation. The results of the analysis demonstrate that inhibition of sumoylation with ginkgolic acid (GA) arrests the G2/M1 transition in mouse spermatocytes preventing chromosome condensation and disassembling of the synaptonemal complex. Our results revealed that the activity of PLK1 and the Aurora kinases increased during the G2/M1 meiotic transition, but was negatively regulated by the inhibition of sumoylation. In the same experiment, the activity of c-Abl, the ERKs, and AKT were not affected or increased after GA treatment. Both the AURKs and PLK1 appear to be "at the right place, at the right time" to at least, in part, explain the meiotic arrest obtained in the spermatocyte culture.
Topics: Animals; Cell Cycle Checkpoints; Cells, Cultured; Male; Mice; Mice, Inbred C57BL; Phosphorylation; Phosphotransferases; Receptor Cross-Talk; Small Ubiquitin-Related Modifier Proteins; Spermatocytes; Sumoylation
PubMed: 28435066
DOI: 10.1016/j.bbrc.2017.04.107 -
Trends in Biochemical Sciences May 2023Protein SUMOylation is one of the most prevalent post-translational modifications (PTMs) and important for maintaining cellular homeostasis in response to various...
Protein SUMOylation is one of the most prevalent post-translational modifications (PTMs) and important for maintaining cellular homeostasis in response to various cellular stresses. Emerging evidence reveals the role of liquid-liquid phase separation (LLPS)/biomolecular condensates in cellular SUMOylation, potentially solving a puzzle regarding the cellular mechanism of SUMOylation regulation.
Topics: Sumoylation; Protein Processing, Post-Translational
PubMed: 36621339
DOI: 10.1016/j.tibs.2022.12.003 -
Genetics Jul 2022In Drosophila, Toll/NF-κB signaling plays key roles in both animal development and in host defense. The activation, intensity, and kinetics of Toll signaling are...
In Drosophila, Toll/NF-κB signaling plays key roles in both animal development and in host defense. The activation, intensity, and kinetics of Toll signaling are regulated by posttranslational modifications such as phosphorylation, SUMOylation, or ubiquitination that target multiple proteins in the Toll/NF-κB cascade. Here, we have generated a CRISPR-Cas9 edited Dorsal (DL) variant that is SUMO conjugation resistant. Intriguingly, embryos laid by dlSCR mothers overcome dl haploinsufficiency and complete the developmental program. This ability appears to be a result of higher transcriptional activation by DLSCR. In contrast, SUMOylation dampens DL transcriptional activation, ultimately conferring robustness to the dorso-ventral program. In the larval immune response, dlSCR animals show an increase in crystal cell numbers, stronger activation of humoral defense genes, and high cactus levels. A mathematical model that evaluates the contribution of the small fraction of SUMOylated DL (1-5%) suggests that it acts to block transcriptional activation, which is driven primarily by DL that is not SUMO conjugated. Our findings define SUMO conjugation as an important regulator of the Toll signaling cascade, in both development and host defense. Our results broadly suggest that SUMO attenuates DL at the level of transcriptional activation. Furthermore, we hypothesize that SUMO conjugation of DL may be part of a Ubc9-dependent mechanism that restrains Toll/NF-κB signaling.
Topics: Animals; Drosophila; Drosophila Proteins; NF-kappa B; Signal Transduction; Sumoylation
PubMed: 35567478
DOI: 10.1093/genetics/iyac081 -
Essays in Biochemistry 2012PTMs (post-translational modifications) of lysine residues have proven to be major regulators of gene expression, protein-protein interactions, and protein processing... (Review)
Review
PTMs (post-translational modifications) of lysine residues have proven to be major regulators of gene expression, protein-protein interactions, and protein processing and degradation. This is of particular importance in regulating the cytoskeleton, an enormously complex system of proteins responsible for cell motility, intracellular trafficking, and maintenance of cell form and structure. The cytoskeleton is present in all cells, including eukaryotes and prokaryotes, and comprises structures such as flagella, cilia and lamellipodia which play critical roles in intracellular transport and cellular division. Cytoskeletal regulation relies on numerous multi-component assemblies. In this chapter, we focus on the regulation of the cytoskeleton by means of PTMs of lysine residues on the cytoskeletal subunits and their accessory proteins. We specifically address the three main classes of cytoskeletal proteins in eukaryotes that polymerize into filaments, including microfilaments (actin filaments), intermediate filaments and microtubules. We discuss the identification and biological importance of lysine acetylation, a regulator of all three filament types. We also review additional lysine modifications, such as ubiquitination and SUMOylation, and their role in protein regulation and processing.
Topics: Actin Cytoskeleton; Animals; Cytoskeleton; Humans; Lysine; Protein Processing, Post-Translational; Sumoylation; Ubiquitination
PubMed: 22708568
DOI: 10.1042/bse0520135 -
International Journal of Oncology Sep 2021The small ubiquitin‑like modifier (SUMO) system serves an important role in the regulation of protein stability and function. SUMOylation sustains the homeostatic... (Review)
Review
The small ubiquitin‑like modifier (SUMO) system serves an important role in the regulation of protein stability and function. SUMOylation sustains the homeostatic equilibrium of protein function in normal tissues and numerous types of tumor. Accumulating evidence has revealed that SUMO enzymes participate in carcinogenesis via a series of complex cellular or extracellular processes. The present review outlines the physiological characteristics of the SUMOylation pathway and provides examples of SUMOylation participation in different cancer types, including in hematological malignancies (leukemia, lymphoma and myeloma). It has been indicated that the SUMO pathway may influence chromosomal instability, cell cycle progression, apoptosis and chemical drug resistance. The present review also discussed the possible relationship between SUMOylation and carcinogenic mechanisms, and evaluated their potential as biomarkers and therapeutic targets in the diagnosis and treatment of hematological malignancies. Developing and investigating inhibitors of SUMO conjugation in the future may offer promising potential as novel therapeutic strategies.
Topics: Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Hematologic Neoplasms; Humans; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Sumoylation
PubMed: 34368858
DOI: 10.3892/ijo.2021.5253 -
Cell Death & Disease Oct 2021MAPK/p38 is an important mammalian signaling cascade that responds to a variety of intracellular or extracellular stimuli, such as reactive oxygen species (ROS), and...
MAPK/p38 is an important mammalian signaling cascade that responds to a variety of intracellular or extracellular stimuli, such as reactive oxygen species (ROS), and participates in numerous physiological and pathological processes. However, the biological function of p38 in different tumors, and even at different stages of the same tumor, remains elusive. To further understand the regulatory mechanism of p38 and oxidative stress in the occurrence and development of gastric cancer, we report SUMOylation as a novel post-translational modification occurring on lysine 152 of MAPK14/p38α through immunoprecipitation and series of pull-down assays in vitro and in vivo. Importantly, we determine that p38α-SUMOylation functions as an authentic sensor and accelerator of reactive oxygen species generation via interaction with and activation of MK2 in the nucleus, and the ROS accumulation, in turn, promotes the SUMOylation of p38α by stabilizing the PIASxα protein. This precise regulatory mechanism is exploited by gastric cancer cells to create an internal environment for survival and, ultimately, metastasis. This study reveals novel insights into p38α-SUMOylation and its association with the intracellular oxidative stress response, which is closely related to the processes of gastric cancer. Furthermore, the PIASxα/p38α-SUMOylation/MK2 cis-axis may serve as a desirable therapeutic target in gastric cancer as targeting PIASxα, MK2, or a specific peptide region of p38α may reconcile the aberrant oxidative stress response in gastric cancer cells.
Topics: Animals; Female; Humans; Mice; Neoplasm Metastasis; Reactive Oxygen Species; Stomach Neoplasms; Sumoylation; p38 Mitogen-Activated Protein Kinases
PubMed: 34686655
DOI: 10.1038/s41419-021-04302-6 -
Cancer Biology & Therapy 2019Angiogenesis is the process of endothelial cell migration and proliferation induced by angiogenic factors, which is essential for the development of tumors. In recent... (Review)
Review
Angiogenesis is the process of endothelial cell migration and proliferation induced by angiogenic factors, which is essential for the development of tumors. In recent years, studies have reported that SUMOylation acts on tumor angiogenesis by targeting angiogenic factors as one of post-translational modifications of proteins. Anti-angiogenic therapy is a new treatment method for tumor treatment following radiotherapy and chemotherapy, and it inhibits tumor growth by blocking tumor blood vessels. Therefore, SUMOylation may become a potential target for anti-angiogenesis therapy. This article focuses on the effect of SUMOylation on vascular growth factors, important signaling pathways proteins, and the migration and function of endothelial cells, in order to provide a new research idea for the anti-angiogenic therapy of tumors.
Topics: Angiogenesis Inducing Agents; Disease Progression; Humans; Neoplasms; Sumoylation; Survival Rate
PubMed: 30261153
DOI: 10.1080/15384047.2018.1523854 -
International Journal of Molecular... Dec 2021Serotonin 1A receptors (5-HT1ARs) are implicated in the control of mood, cognition, and memory and in various neuropsychiatric disorders such as depression and anxiety....
Serotonin 1A receptors (5-HT1ARs) are implicated in the control of mood, cognition, and memory and in various neuropsychiatric disorders such as depression and anxiety. As such, understanding the regulation of 5-HT1ARs will inform the development of better treatment approaches. We previously demonstrated 5-HT1ARs are SUMOylated by SUMO1 in the rat brain. Agonist stimulation increased SUMOylation and was further enhanced when combined with 17β-estradiol-3-benzoate (EB), which are treatments that cause the transient and prolonged desensitization of 5-HT1AR signaling, respectively. In the current study, we identified the protein inhibitor of activated STAT (PIAS)xα as the enzyme that facilitates SUMOylation, and SENP2 as the protein that catalyzes the deSUMOylation of 5-HT1ARs. We demonstrated that PIASxα significantly increased in the membrane fraction of rats co-treated with EB and an agonist, compared to either the EB-treated or vehicle-treated groups. The acute treatment with an agonist alone shifted the location of SENP2 from the membrane to the cytoplasmic fraction, but it has little effect on PIASxα. Hence, two separate mechanisms regulate SUMOylation and the activity of 5-HT1ARs by an agonist and EB. The effects of EB on 5-HT1AR SUMOylation and signaling may be related to the higher incidence of mood disorders in women during times with large fluctuations in estrogens. Targeting the SUMOylation of 5-HT1ARs could have important clinical relevance for the therapy for several neuropsychiatric disorders in which 5-HT1ARs are implicated.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Line; Cell Membrane; Cytoplasm; Estradiol; Female; Gene Expression Regulation; Protein Inhibitors of Activated STAT; Rats; Receptor, Serotonin, 5-HT1A; Sumoylation; Ubiquitin-Protein Ligases; Up-Regulation
PubMed: 34947973
DOI: 10.3390/ijms222413176 -
Advanced Science (Weinheim,... Mar 2024Pathological cardiac hypertrophy is the leading cause of heart failure and has an extremely complicated pathogenesis. TEA domain transcription factor 1 (TEAD1) is...
Pathological cardiac hypertrophy is the leading cause of heart failure and has an extremely complicated pathogenesis. TEA domain transcription factor 1 (TEAD1) is recognized as an important transcription factor that plays a key regulatory role in cardiovascular disease. This study aimed to explore the role of TEAD1 in cardiac hypertrophy and to clarify the regulatory role of small ubiquitin-like modifier (SUMO)-mediated modifications. First, the expression level of TEAD1 in patients with heart failure, mice, and cardiomyocytes is investigated. It is discovered that TEAD1 is modified by SUMO1 during cardiac hypertrophy and that the process of deSUMOylation is regulated by SUMO-specific protease 1 (SENP1). Lysine 173 is an essential site for TEAD1 SUMOylation, which affects the protein stability, nuclear localization, and DNA-binding ability of TEAD1 and enhances the interaction between TEAD1 and its transcriptional co-activator yes-associated protein 1 in the Hippo pathway. Finally, adeno-associated virus serotype 9 is used to construct TEAD1 wild-type and KR mutant mice and demonstrated that the deSUMOylation of TEAD1 markedly exacerbated cardiomyocyte enlargement in vitro and in a mouse model of cardiac hypertrophy. The results provide novel evidence that the SUMOylation of TEAD1 is a promising therapeutic strategy for hypertrophy-related heart failure.
Topics: Humans; Mice; Animals; Sumoylation; Cardiomegaly; Transcription Factors; Heart Failure; Gene Expression Regulation; TEA Domain Transcription Factors
PubMed: 38225750
DOI: 10.1002/advs.202305677