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Pias1 is essential for erythroid and vascular development in the mouse embryo.

The protein inhibitor of activated STAT-1 (PIAS1) is one of the few known SUMO E3 ligases. PIAS1 has been implicated in several biological processes including repression of innate immunity and DNA repair. However, PIAS1 function during development and tissue differentiation has not been studied. Here, we report that Pias1 is required for proper embryonic development. Approximately 90% of Pias1 null embryos die in utero between E10.5 and E12.5. We found significant apoptosis within the yolk sac (YS) blood vessels and concomitant loss of red blood cells (RBCs) resulting in profound anemia. In ad

Посттрансляционные изменения в нейроиммунных клетках во время нейроинфламмации: комплексные сети регулирования и терапевтические возможности.

Нейроинфламмация представляет собой общий патологический механизм, лежащий в основе широкого спектра нарушений центральной нервной системы (КНС), включая нейродегенеративные расстройства (НДД), ишемический инсульт (ИС), травматическое повреждение мозга (ТБИ) и демиелионирующие заболевания, такие как множественный склероз (МС). Этот процесс начинается с организованной реакции микроглий, астроцитов, олигодендроцитов, нейронов, эндотелиальных клеток головного мозга и проникновения в периферийные иммунные клетки. Нейроинфламмация может облегчить ремонт тканей или, наоборот, увековечить хроническое

Совпадение в аннотации оригинала
Neuroinflammation represents a common pathological mechanism underlying a wide range of central nervous system (CNS) disorders, encompassing … se. In this review, we synthesize evidence on various PTMs such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, glycosylation, S-nitrosylation (SNO), and metabolite-coupled modifications, including lactylation and succinylation. We analyze their convergent and divergent roles across different neuroimmune cell types, disease-related …

Complex roles for proliferating cell nuclear antigen in restricting human cytomegalovirus replication.

DNA viruses at once elicit and commandeer host pathways, including DNA repair pathways, for virus replication. Despite encoding its own DNA … PCNA is poorly understood. PCNA function in DNA repair is regulated by monoubiquitination (mUb) or SUMOylation of PCNA at lysine 164 (K164). We find that mUb-PCNA increases over the course of infection, and modification of K164 is required for PCNA-mediated restriction of virus replication. mUb-PCNA plays important known roles in recruiting TLS polymerases t …

Polarized benzene rings can promote the interaction between CaM and the CaMBD region of nNOS.

INTRODUCTION: The neuronal nitric oxide synthase (nNOS) subtype of nitric oxide synthase (NOS) is an enzyme required for learning and memory … erification of the antagonistic competitive mechanism between CaM allosteric activation of nNOS and SUMOylation hyperactivation was performed. DISCUSSION: In summary, this study explored the ability and mode of action of key residues in nNOS-CaMBD on the binding of interfering peptides to CaM, thereby providing new structural perspectives for the activation …

E1B-55K-Mediated Regulation of RNF4 SUMO-Targeted Ubiquitin Ligase Promotes Human Adenovirus Gene Expression.

Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB-associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-de

Visualizing and quantifying protein polySUMOylation at the single-molecule level.

Protein polySUMOylation, the attachment of small ubiquitin-like modifier (SUMO) chains to the target protein, is associated with a variety of physiological processes. However, the analysis of protein polySUMOylation is often complicated by the heterogeneity of SUMO-target conjugates. Here, we develop a new strategy to visualize and quantify polySUMOylation at the single-molecule level by integrating the tetracysteine (TC) tag labeling technology and total internal reflection fluorescence (TIRF)-based single-molecule imaging. As a proof-of-concept, we employ the human SUMO-2 as the model. The a…

Controlling the master-upstream regulation of the tumor suppressor LKB1.

The tumor suppressor LKB1 is an essential serine/threonine kinase, which regulates various cellular processes such as cell metabolism, cell proliferation, cell polarity, and cell migration. Germline mutations in the STK11 gene (encoding LKB1) are the cause of the Peutz-Jeghers syndrome, which is characterized by benign polyps in the intestine and a higher risk for the patients to develop intestinal and extraintestinal tumors. Moreover, mutations and misregulation of LKB1 have been reported to occur in most types of tumors and are among the most common aberrations in lung cancer. LKB1 activates

MITF E318K's effect on melanoma risk independent of, but modified by, other risk factors.

A rare germline variant in the microphthalmia-associated transcription factor (MITF) gene, E318K, has been reported as associated with melanoma. We confirmed its independent association with melanoma [odds ratio (OR) 1.7, 95% confidence interval (CI) = 1.1, 2.7, P = 0.03]; adjusted for age, sex, center, age × sex interaction, pigmentation characteristics, family history of melanoma, and nevus density). In stratified analyses, carriage of MITF E318K was associated with melanoma more strongly in people with dark hair than fair hair (P for interaction, 0.03) and in those with no moles than some o

Identification of aberrantly methylated differentially expressed genes and pro-tumorigenic role of KIF2C in melanoma.

Background: Skin Cutaneous Melanoma (SKCM) is known as an aggressive malignant cancer, which could be directly derived from melanocytic nevi … s, cell proliferation, cell division, phosphorylation, extracellular matrix disassembly and protein sumoylation. Pathway enrichment showed selenocompound metabolism, small cell lung cancer and lysosome. Hypermethylation-downregulated genes were enriched in biological processes of positive regulation of transcription from RNA polymerase II promoter, cell adhes …

Cardiac-targeted PIASy gene silencing mediates deSUMOylation of caveolin-3 and prevents ischemia/reperfusion-induced Nav1.5 downregulation and ventricular arrhythmias.

BACKGROUND: Abnormal myocardial Nav1.5 expression and function cause lethal ventricular arrhythmias during myocardial ischemia-reperfusion ( … and after H/R in HEK293T cells. CONCLUSIONS: I/R-induced cardiac PIASy activation increased Cav-3 SUMOylation by SUMO2/3 and dysregulated Nav1.5-related ventricular arrhythmias. Cardiac-targeted PIASy silencing mediated Cav-3 deSUMOylation and partially prevented I/R-induced Nav1.5 downregulation in the plasma membrane of cardiomyocytes, and subsequent vent …

MxA Mediates SUMO-Induced Resistance to Vesicular Stomatitis Virus.

UNLABELLED: Multiple cellular pathways are regulated by small ubiquitin-like modifier (SUMO) modification, including ubiquitin-mediated prot … -VSV effect of SUMO. Furthermore, SUMO expression resulted in interferon-regulatory factor 3 (IRF3) SUMOylation, subsequently decreasing RABV-induced IRF3 phosphorylation and interferon synthesis. As expected, this rendered SUMO-expressing cells more sensitive to RABV infection, even though MxA was stabilized in SUMO-expressing cells, since its expression did …

Rhabdoviruses, Antiviral Defense, and SUMO Pathway.

Small Ubiquitin-like MOdifier (SUMO) conjugation to proteins has essential roles in several processes including localization, stability, and function of several players implicated in intrinsic and innate immunity. In human, five paralogs of SUMO are known of which three are ubiquitously expressed (SUMO1, 2, and 3). Infection by rhabdoviruses triggers cellular responses through the activation of pattern recognition receptors, which leads to the production and secretion of interferon. This review will focus on the effects of the stable expression of the different SUMO paralogs or Ubc9 depletion

The SMN Tudor SIM-like domain is key to SmD1 and coilin interactions and to Cajal body biogenesis.

Cajal bodies (CBs) are nuclear organelles involved in the maturation of spliceosomal small nuclear ribonucleoproteins (snRNPs). They concentrate coilin, snRNPs and the survival motor neuron protein (SMN). Dysfunction of CB assembly occurs in spinal muscular atrophy (SMA). Here, we demonstrate that SMN is a SUMO1 target that has a small ubiquitin-related modifier (SUMO)-interacting motif (SIM)-like motif in the Tudor domain. The expression of SIM-like mutant constructs abolishes the interaction of SMN with the spliceosomal SmD1 (also known as SNRPD1), severely decreases SMN-coilin interaction a

Post-translational modification of proteins in the human testis development pathway.

BACKGROUND: The foetal testes produce the androgens necessary to masculinise the developing embryo and support the maturation of germ cells, … elbourne library for peer-reviewed English-language studies using keywords such as phosphorylation, SUMOylation, acetylation, ubiquitination alongside each protein of interest. PTM sites in proteins involved in testis development were identified using the PhosphoSitePlus database focusing those confirmed in in vitro or animal model studies. ClinVar and the Hu …

Regulation of the DNA damage response on male meiotic sex chromosomes.

During meiotic prophase in males, the sex chromosomes partially synapse to form the XY body, a unique structure that recruits proteins involved in the DNA damage response, which is believed to be important for silencing of the sex chromosomes. It remains elusive how the DNA damage response in the XY body is regulated. Here we show that H2AX-MDC1-RNF8 signaling, which is well characterized in somatic cells, is dispensable for the recruitment of proteins to the unsynapsed axes in the XY body. On the other hand, the DNA damage response that spreads over the sex chromosomes is largely similar to t

MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis.

The possible association between the membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1) and inflammation has been suggested, but the molecular mechanisms underlying this link, especially during atherogenesis, remain unclear. In endothelial cells (ECs) exposed to disturbed flow (d-flow), p90 ribosomal S6 kinase (p90RSK) bound to MAGI1, causing MAGI1-S741 phosphorylation and sentrin/SUMO-specific protease 2 T368 phosphorylation-mediated MAGI1-K931 deSUMOylation. MAGI1-S741 phosphorylation upregulated EC activation via activating Rap1. MAGI1-K931 deSUMOylation induced b…

Mitochondrial ROS-induced ERK1/2 activation and HSF2-mediated AT1 R upregulation are required for doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX), one useful chemotherapeutic agent, is limited in clinical use because of its serious cardiotoxicity. Growing evidence sug … ocytes were damaged by DOX. Furthermore, the DNA binding activity of HSF2 was enhanced by DOX via deSUMOylation. Overexpression of HSF2 enhanced DOX-induced cardiomyocyte cell death as well. Taken together, we found that DOX induced mitochondrial ROS release to activate ERK-mediated HSF2 nuclear translocation and AT1 R upregulation causing DOX-damaged heart f …

Ubiquitin and SUMO conjugation as biomarkers of acute myeloid leukemias response to chemotherapies.

Ubiquitin and the ubiquitin-like SUMO are covalently conjugated to thousands of proteins to modulate their function and fate. Many of the enzymes involved in their conjugation are dysregulated in cancers and involved in cancer cell response to therapies. We describe here the identification of biomarkers of the activity of these enzymes and their use to predict acute myeloid leukemias (AML) response to standard chemotherapy (daunorubicin-DNR and cytarabine-Ara-C). We compared the ability of extracts from chemosensitive and chemoresistant AML cells to conjugate ubiquitin or SUMO-1 on 9,000 prote

Unveiling the role of histone deacetylases in neurological diseases: focus on epilepsy.

Epilepsy remains a prevalent chronic neurological disease that is featured by aberrant, recurrent and hypersynchronous discharge of neurons and poses a great challenge to healthcare systems. Although several therapeutic interventions are successfully utilized for treating epilepsy, they can merely provide symptom relief but cannot exert disease-modifying effect. Therefore, it is of urgent need to explore other potential mechanism to develop a novel approach to delay the epileptic progression. Since approximately 30 years ago, histone deacetylases (HDACs), the versatile epigenetic regulators re

Совпадение в полном тексте источника
… Sumoylation . … In particular, the contribution of HDAC4 to the sumoylation for MEF2 finally leads to transcription inhibition [ 80 ] while HDAC4-mediated sumoylation of ZXDC activates the transcription activity [ 81 ]. …

Nuclear-Cytoplasmic Axis in Cancer: From Protein Mislocalization to Anticancer Drug Resistance.

Nucleocytoplasmic transport (NCT) regulates the spatial distribution of proteins and RNA between the nucleus and cytoplasm. NCT dysregulation can mislocalize tumor suppressors, DNA-repair factors, transcription factors, and drug targets in cancer. In this review, we conceptualize NCT-dependent protein mislocalization as a spatial regulatory framework for anticancer drug resistance, rather than as a catalogue of transport components. We systematically discuss how nuclear pore complex (NPC) remodeling, transport-receptor imbalance, post-translational modification (PTM)-regulated cargo routing, s

Совпадение в полном тексте источника
… SUMOylation Small ubiquitin-like modifier (SUMO)ylation is crucial for protein localization and stability, thus influencing therapeutic response [ 73 ]. Aberrant SUMOylation may alter subcellular partitioning of target proteins, leading to acquired drug resistance. … | TOP1 | Camptothecin-induced SUMOylation alters TOP1 partitioning between nucleoplasm and nucleoli, reducing effective TOP1 availability and conferring acquired resistance. | Cancer cells | [ 74 ] p27^Kip1 | Hyper-SUMOylation enhances nuclear export and cytoplasmic retention of p27^Kip1, impairing …