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Cell Systems Jan 2021We performed RNA-seq and high-resolution mass spectrometry on 128 blood samples from COVID-19-positive and COVID-19-negative patients with diverse disease severities and...
We performed RNA-seq and high-resolution mass spectrometry on 128 blood samples from COVID-19-positive and COVID-19-negative patients with diverse disease severities and outcomes. Quantified transcripts, proteins, metabolites, and lipids were associated with clinical outcomes in a curated relational database, uniquely enabling systems analysis and cross-ome correlations to molecules and patient prognoses. We mapped 219 molecular features with high significance to COVID-19 status and severity, many of which were involved in complement activation, dysregulated lipid transport, and neutrophil activation. We identified sets of covarying molecules, e.g., protein gelsolin and metabolite citrate or plasmalogens and apolipoproteins, offering pathophysiological insights and therapeutic suggestions. The observed dysregulation of platelet function, blood coagulation, acute phase response, and endotheliopathy further illuminated the unique COVID-19 phenotype. We present a web-based tool (covid-omics.app) enabling interactive exploration of our compendium and illustrate its utility through a machine learning approach for prediction of COVID-19 severity.
Topics: Aged; Aged, 80 and over; COVID-19; Cohort Studies; Female; Gelsolin; Humans; Inflammation Mediators; Machine Learning; Male; Middle Aged; Neutrophils; Principal Component Analysis; Sequence Analysis, RNA; Severity of Illness Index
PubMed: 33096026
DOI: 10.1016/j.cels.2020.10.003 -
Cell Jul 2021Cross-presentation of antigens from dead tumor cells by type 1 conventional dendritic cells (cDC1s) is thought to underlie priming of anti-cancer CD8 T cells. cDC1...
Cross-presentation of antigens from dead tumor cells by type 1 conventional dendritic cells (cDC1s) is thought to underlie priming of anti-cancer CD8 T cells. cDC1 express high levels of DNGR-1 (a.k.a. CLEC9A), a receptor that binds to F-actin exposed by dead cell debris and promotes cross-presentation of associated antigens. Here, we show that secreted gelsolin (sGSN), an extracellular protein, decreases DNGR-1 binding to F-actin and cross-presentation of dead cell-associated antigens by cDC1s. Mice deficient in sGsn display increased DNGR-1-dependent resistance to transplantable tumors, especially ones expressing neoantigens associated with the actin cytoskeleton, and exhibit greater responsiveness to cancer immunotherapy. In human cancers, lower levels of intratumoral sGSN transcripts, as well as presence of mutations in proteins associated with the actin cytoskeleton, are associated with signatures of anti-cancer immunity and increased patient survival. Our results reveal a natural barrier to cross-presentation of cancer antigens that dampens anti-tumor CD8 T cell responses.
Topics: Actins; Amino Acid Sequence; Animals; Antigens, Neoplasm; CD8-Positive T-Lymphocytes; Cell Movement; Cell Proliferation; Cross-Priming; Cytoskeleton; Dendritic Cells; Gelsolin; Gene Expression Regulation, Neoplastic; Immune Checkpoint Inhibitors; Immunity; Lectins, C-Type; Mice, Inbred C57BL; Mutation; Neoplasms; Protein Binding; Receptors, Immunologic; Receptors, Mitogen; Survival Analysis; Mice
PubMed: 34081922
DOI: 10.1016/j.cell.2021.05.021 -
The Journal of Biological Chemistry 2021Actin is a major intracellular protein with key functions in cellular motility, signaling, and structural rearrangements. Its dynamic behavior, such as polymerization...
Actin is a major intracellular protein with key functions in cellular motility, signaling, and structural rearrangements. Its dynamic behavior, such as polymerization and depolymerization of actin filaments in response to intracellular and extracellular cues, is regulated by an abundance of actin binding proteins. Out of these, gelsolin is one of the most potent for filament severing. However, myosin motor activity also fragments actin filaments through motor-induced forces, suggesting that these two proteins could cooperate to regulate filament dynamics and motility. To test this idea, we used an in vitro motility assay, where actin filaments are propelled by surface-adsorbed heavy meromyosin (HMM) motor fragments. This allows studies of both motility and filament dynamics using isolated proteins. Gelsolin, at both nanomolar and micromolar Ca concentration, appreciably enhanced actin filament severing caused by HMM-induced forces at 1 mM MgATP, an effect that was increased at higher HMM motor density. This finding is consistent with cooperativity between actin filament severing by myosin-induced forces and by gelsolin. We also observed reduced sliding velocity of the HMM-propelled filaments in the presence of gelsolin, providing further support of myosin-gelsolin cooperativity. Total internal reflection fluorescence microscopy-based single molecule studies corroborated that the velocity reduction was a direct effect of gelsolin binding to the filament and revealed different filament severing pattern of stationary and HMM propelled filaments. Overall, the results corroborate cooperative effects between gelsolin-induced alterations in the actin filaments and changes due to myosin motor activity leading to enhanced F-actin severing of possible physiological relevance.
Topics: Actin Cytoskeleton; Actomyosin; Animals; Gelsolin; Humans; Myosin Type II; Myosins; Protein Binding; Rabbits
PubMed: 33303625
DOI: 10.1074/jbc.RA120.015863 -
The Kaohsiung Journal of Medical... Sep 2022The protein expression of gelsolin, an actin scavenger controlling cytoskeletal remodeling, cell morphology, differentiation, movement, and apoptosis, has been found to... (Review)
Review
The protein expression of gelsolin, an actin scavenger controlling cytoskeletal remodeling, cell morphology, differentiation, movement, and apoptosis, has been found to be significantly decreased in several pathological conditions including neurodegenerative diseases, inflammatory disorders, and cancers. Its extracellular isoform, called plasma gelsolin (pGSN), is one of the most abundant plasma proteins in the circulation, and has emerged as a novel diagnostic biomarker for early disease detection. Current evidence reveals that gelsolin can function as either an oncoprotein or a tumor suppressor depending on the carcinoma type. Interestingly, recent studies have shown that pGSN is also involved in immunomodulation, revealing the multifunctional roles of pGSN in tumor progression. In this review, we discuss the current knowledge focusing on the roles of gelsolin in inflammation and wound healing, cancers, and tumor microenvironment. Future prospects of pGSN related studies and clinical application are also addressed.
Topics: Carcinogenesis; Gelsolin; Humans; Inflammation; Neoplasms; Tumor Microenvironment
PubMed: 35942641
DOI: 10.1002/kjm2.12578 -
Cells Oct 2022Ovarian Cancer (OVCA) is the most fatal gynecologic cancer and has a 5-year survival rate less than 45%. This is mainly due to late diagnosis and drug resistance.... (Review)
Review
Ovarian Cancer (OVCA) is the most fatal gynecologic cancer and has a 5-year survival rate less than 45%. This is mainly due to late diagnosis and drug resistance. Overexpression of plasma gelsolin (pGSN) is key contributing factor to OVCA chemoresistance and immunosuppression. Gelsolin (GSN) is a multifunctional protein that regulates the activity of actin filaments by cleavage, capping, and nucleation. Generally, it plays an important role in cytoskeletal remodeling. GSN has three isoforms: cytosolic GSN, plasma GSN (pGSN), and gelsolin-3. Exosomes containing pGSN are released and contribute to the progression of OVCA. This review describes how pGSN overexpression inhibits chemotherapy-induced apoptosis and triggers positive feedback loops of pGSN expression. It also describes the mechanisms by which exosomal pGSN promotes apoptosis and dysfunction in tumor-killing immune cells. A discussion on the potential of pGSN as a prognostic, diagnostic, and therapeutic marker is also presented herein.
Topics: Female; Humans; Gelsolin; Drug Resistance, Neoplasm; Tumor Microenvironment; Ovarian Neoplasms; Antineoplastic Agents
PubMed: 36291171
DOI: 10.3390/cells11203305 -
Scientific Reports Sep 2018Woundhealing disorders characterized by impaired or delayed re-epithelialization are a serious medical problem that is painful and difficult to treat. Gelsolin (GSN), a...
Woundhealing disorders characterized by impaired or delayed re-epithelialization are a serious medical problem that is painful and difficult to treat. Gelsolin (GSN), a known actin modulator, supports epithelial cell regeneration and apoptosis. The aim of this study was to estimate the potential of recombinant gelsolin (rhu-pGSN) for ocular surface regeneration to establish a novel therapy for delayed or complicated wound healing. We analyzed the influence of gelsolin on cell proliferation and wound healing in vitro, in vivo/ex vivo and by gene knockdown. Gelsolin is expressed in all tested tissues of the ocular system as shown by molecular analysis. The concentration of GSN is significantly increased in tear fluid samples of patients with dry eye disease. rhu-pGSN induces cell proliferation and faster wound healing in vitro as well as in vivo/ex vivo. TGF-β dependent transcription of SMA is significantly decreased after GSN gene knockdown. Gelsolin is an inherent protein of the ocular system and is secreted into the tear fluid. Our results show a positive effect on corneal cell proliferation and wound healing. Furthermore, GSN regulates the synthesis of SMA in myofibroblasts, which establishes GSN as a key protein of TGF-β dependent cell differentiation.
Topics: Actins; Animals; Cell Differentiation; Cell Proliferation; Conjunctiva; Cornea; Dry Eye Syndromes; Epithelial Cells; Eyelids; Female; Gelsolin; Gene Expression Regulation; Humans; Lacrimal Apparatus; Male; Mice; Myofibroblasts; Nasolacrimal Duct; RNA, Small Interfering; Re-Epithelialization; Signal Transduction; Transforming Growth Factor beta; Wound Healing
PubMed: 30177722
DOI: 10.1038/s41598-018-31441-2 -
The Journal of Neuroscience : the... Mar 2022Myelin is essential to neuronal health and CNS function, and oligodendrocytes (OLs) undergo a complex process of cytoskeletal remodeling to form compact myelin sheaths....
Myelin is essential to neuronal health and CNS function, and oligodendrocytes (OLs) undergo a complex process of cytoskeletal remodeling to form compact myelin sheaths. We previously discovered that a formin protein, Dishevelled associated activator of morphogenesis 2 (Daam2), suppresses OL differentiation through Wnt signaling; however, its role in cytoskeletal control remains unknown. To investigate this, we used OL-specific Daam2 conditional knockout (Daam2 cKO) mice of either sex and found myelin decompaction during an active period of myelination in postnatal development and motor coordination deficits in adulthood. Using primary OL cultures, we found Daam2-depleted OLs showed morphologic dysregulation during differentiation, suggesting that Daam2 regulates the OL cytoskeleton. screening identified the actin regulators Rac1 and Gelsolin as possible effectors in Daam2-deficient OL cytoskeletal regulation. Using gain-of-function and loss-of-function (LOF) experiments in primary OLs, we found that Rac1 and Gelsolin operate downstream of Daam2 in OL differentiation, with Gelsolin and Daam2 promoting and inhibiting membrane spreading during late differentiation, respectively. experiments using Daam2 cKO mice revealed increased protein levels of Gelsolin in the developing white matter with no change in RNA levels, suggesting that Daam2 acts in a posttranslational manner to suppress Gelsolin levels. biochemical studies show Daam2 induces Gelsolin ubiquitination and degradation in OLs. Together, our studies show Daam2 is essential for formation of functional myelin through modulation of Gelsolin levels to regulate the OL cytoskeleton. These findings further demonstrate the critical role of cytoskeletal dynamics in myelination and reveal novel avenues for treatment of a variety of white matter diseases. Proper myelin formation is essential to CNS function, and oligodendrocytes (OLs) require extensive changes in the actin cytoskeleton to form myelin sheaths. Here, we show that the formin protein Dishevelled associated activator of morphogenesis 2 (Daam2) is necessary for myelin compaction during development and motor learning in adulthood. Further, we demonstrate that Daam2 regulates OL differentiation and morphology through actin regulators Rac1 and Gelsolin. Lastly, we find that Daam2 may control myelin compaction by modulating the ubiquitination and degradation of Gelsolin through recruitment of the E3 ubiquitin ligase Nedd4. These findings reveal novel pathways for regulating myelin structure and function during white matter development.
Topics: Actin Cytoskeleton; Actins; Animals; Cell Differentiation; Gelsolin; Mice; Microfilament Proteins; Myelin Sheath; Neuropeptides; Oligodendroglia; rac1 GTP-Binding Protein; rho GTP-Binding Proteins
PubMed: 35101966
DOI: 10.1523/JNEUROSCI.1517-21.2022 -
International Journal of Molecular... Aug 2018Gelsolin, an actin-depolymerizing protein expressed both in extracellular fluids and in the cytoplasm of a majority of human cells, has been recently implicated in a... (Review)
Review
Gelsolin, an actin-depolymerizing protein expressed both in extracellular fluids and in the cytoplasm of a majority of human cells, has been recently implicated in a variety of both physiological and pathological processes. Its extracellular isoform, called plasma gelsolin (pGSN), is present in blood, cerebrospinal fluid, milk, urine, and other extracellular fluids. This isoform has been recognized as a potential biomarker of inflammatory-associated medical conditions, allowing for the prediction of illness severity, recovery, efficacy of treatment, and clinical outcome. A compelling number of animal studies also demonstrate a broad spectrum of beneficial effects mediated by gelsolin, suggesting therapeutic utility for extracellular recombinant gelsolin. In the review, we summarize the current data related to the potential of pGSN as an inflammatory predictor and therapeutic target, discuss gelsolin-mediated mechanisms of action, and highlight recent progress in the clinical use of pGSN.
Topics: Animals; Biomarkers; Disease Models, Animal; Disease Susceptibility; Female; Gelsolin; Humans; Inflammation; Male; Neoplasms; Pregnancy; Prognosis; Severity of Illness Index; Treatment Outcome
PubMed: 30149613
DOI: 10.3390/ijms19092516 -
Placenta Aug 2023(1) OBJECTIVE: discover new candidate biomarkers for spontaneous preterm birth in early pregnancy samples. When fully clinically validated, early pregnancy biomarkers...
(1) OBJECTIVE: discover new candidate biomarkers for spontaneous preterm birth in early pregnancy samples. When fully clinically validated, early pregnancy biomarkers for sPTB give the possibility to intervene or monitor high-risk pregnancies more intensively through, as example, pelvic exams, ultrasound or sonographic cervical length surveillance. (2) STUDY DESIGN: Early pregnancy serum samples of eight spontaneous extreme and very preterm birth cases (<32 weeks of gestational age) without any symptoms of preeclampsia and fetal growth restriction and eight uncomplicated pregnancies were analyzed by liquid chromatography mass spectrometry (LC-MS). Thirteen proteins, which were differentially expressed according to the LC-MS data, were subsequently selected for confirmation by enzyme-linked immunosorbent assay (ELISA). (3) RESULTS: Differential expression of four candidate biomarkers was confirmed by ELISA with decreased early pregnancy levels of gelsolin and fibulin-1 and increased levels of c-reactive protein and complement C5 in the preterm birth group. (4) CONCLUSIONS: The confirmed candidate biomarkers are all to some extent related to inflammatory pathways and/or the complement system. This supports the hypothesis that both play a role in extreme and very preterm birth without any symptoms of preeclampsia and fetal growth restriction. The predictive value of complement C5, c-reactive protein, fibulin-1 and gelsolin should, therefore, be validated in another cohort with early pregnancy samples.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Premature Birth; Fetal Growth Retardation; C-Reactive Protein; Gelsolin; Pre-Eclampsia; Biomarkers
PubMed: 37356366
DOI: 10.1016/j.placenta.2023.06.011 -
Cancer Science Jul 2020We have previously shown that gelsolin (GSN) levels are significantly lower in the blood of patients with glioblastoma (GBM) than in healthy controls. Here, we analyzed...
We have previously shown that gelsolin (GSN) levels are significantly lower in the blood of patients with glioblastoma (GBM) than in healthy controls. Here, we analyzed the function of GSN in GBM and examined its clinical significance. Furthermore, microRNAs involved in GSN expression were also identified. The expression of GSN was determined using western blot analysis and found to be significantly lower in GBM samples than normal ones. Gelsolin was mainly localized in normal astrocytes, shown using immunohistochemistry and immunofluorescence. Higher expression of GSN was correlated with more prolonged progression-free survival and overall survival. Gelsolin knockdown using siRNA and shRNA markedly accelerated cell proliferation and invasion in GBM in vitro and in vivo. The inactive form of glycogen synthase kinase-3β was dephosphorylated by GSN knockdown. In GBM tissues, the expression of GSN and microRNA (miR)-654-5p and miR-450b-5p showed an inverse correlation. The miR-654-5p and miR-450b-5p inhibitors enhanced GSN expression, resulting in reduced proliferation and invasion. In conclusion, GSN, which inhibits cell proliferation and invasion, is suppressed by miR-654-5p and miR-450b-5p in GBM, suggesting that these miRNAs can be targets for treating GBM.
Topics: Animals; Apoptosis; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Disease Models, Animal; Female; Gelsolin; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Glioblastoma; Humans; Mice; MicroRNAs; Neoplasm Grading; Phenotype; Prognosis; RNA Interference
PubMed: 32324311
DOI: 10.1111/cas.14429