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1.
Cells ; 11(16)2022 08 22.
Article in English | MEDLINE | ID: covidwho-2023200

ABSTRACT

Obesity is of concern to the population because it is known to cause inflammation and oxidative stress throughout the body, leading to patient predisposition for health conditions such as diabetes, hypertension, and some cancers. However, some proteins that are activated in times of oxidative stress may provide cytoprotective properties. In this study, we aim to gain further understanding of the interconnection between Nrf2 and Sesn2 during obesity-related stress and how this relationship can play a role in cardio-protection. Cardiomyocyte-specific Sesn2 knockout (cSesn2-/-) and Sesn2 overexpressed (tTa-tet-Sesn2) mice and their wildtype littermates (Sesn2flox/flox and tet-Sesn2, respectively) were assigned to either a normal chow (NC) or a high-fat (HF) diet to induce obesity. After 16 weeks of dietary intervention, heart function was evaluated via echocardiography and cardiac tissue was collected for analysis. Immunoblotting, histology, and ROS staining were completed. Human heart samples were obtained via the LifeLink Foundation and were also subjected to analysis. Overall, these results indicated that the overexpression of Sesn2 appears to have cardio-protective effects on the obese heart through the reduction of ROS and fibrosis present in the tissues and in cardiac function. These results were consistent for both mouse and human heart samples. In human samples, there was an increase in Sesn2 and Nrf2 expression in the obese patients' LV tissue. However, there was no observable pattern of Sesn2/Nrf2 expression in mouse LV tissue samples. Further investigation into the link between the Sesn2/Nrf2 pathway and obesity-related oxidative stress is needed.


Subject(s)
Heart Diseases , NF-E2-Related Factor 2 , Animals , Diet, High-Fat , GA-Binding Protein Transcription Factor , Humans , Mice , NF-E2-Related Factor 2/metabolism , Nuclear Proteins/metabolism , Obesity , Reactive Oxygen Species/metabolism , Sestrins
2.
Biochim Biophys Acta Gene Regul Mech ; 1865(7): 194859, 2022 10.
Article in English | MEDLINE | ID: covidwho-1982601

ABSTRACT

Viruses use diverse tactics to hijack host cellular machineries to evade innate immune responses and maintain their life cycles. Being critical transcriptional regulators, human BET proteins are prominent targets of a growing number of viruses. The BET proteins associate with chromatin through the interaction of their bromodomains with acetylated histones, whereas the carboxy-terminal domains of these proteins contain docking sites for various human co-transcriptional regulators. The same docking sites however can be occupied by viral proteins that exploit the BET proteins to anchor their genome components to chromatin in the infected host cell. In this review we highlight the pathological functions of the BET proteins upon viral infection, focusing on the mechanisms underlying their direct interactions with viral proteins, such as the envelope protein from SARS-CoV-2.


Subject(s)
COVID-19 , Histones , Chromatin , Histones/metabolism , Humans , Nuclear Proteins/metabolism , SARS-CoV-2 , Transcription Factors/metabolism , Viral Proteins/genetics
3.
Nucleic Acids Res ; 50(15): 8700-8718, 2022 08 26.
Article in English | MEDLINE | ID: covidwho-1973223

ABSTRACT

FACT (FAcilitates Chromatin Transcription) is a heterodimeric protein complex composed of SUPT16H and SSRP1, and a histone chaperone participating in chromatin remodeling during gene transcription. FACT complex is profoundly regulated, and contributes to both gene activation and suppression. Here we reported that SUPT16H, a subunit of FACT, is acetylated in both epithelial and natural killer (NK) cells. The histone acetyltransferase TIP60 contributes to the acetylation of SUPT16H middle domain (MD) at lysine 674 (K674). Such acetylation of SUPT16H is recognized by bromodomain protein BRD4, which promotes protein stability of SUPT16H in both epithelial and NK cells. We further demonstrated that SUPT16H-BRD4 associates with histone modification enzymes (HDAC1, EZH2), and further regulates their activation status and/or promoter association as well as affects the relevant histone marks (H3ac, H3K9me3 and H3K27me3). BRD4 is known to profoundly regulate interferon (IFN) signaling, while such function of SUPT16H has never been explored. Surprisingly, our results revealed that SUPT16H genetic knockdown via RNAi or pharmacological inhibition by using its inhibitor, curaxin 137 (CBL0137), results in the induction of IFNs and interferon-stimulated genes (ISGs). Through this mechanism, depletion or inhibition of SUPT16H is shown to efficiently inhibit infection of multiple viruses, including Zika, influenza, and SARS-CoV-2. Furthermore, we demonstrated that depletion or inhibition of SUPT16H also causes the remarkable activation of IFN signaling in NK cells, which promotes the NK-mediated killing of virus-infected cells in a co-culture system using human primary NK cells. Overall, our studies unraveled the previously un-appreciated role of FACT complex in coordinating with BRD4 and regulating IFN signaling in both epithelial and NK cells, and also proposed the novel application of the FACT inhibitor CBL0137 to treat viral infections.


Subject(s)
Cell Cycle Proteins/metabolism , Epithelial Cells/metabolism , Interferons/metabolism , Killer Cells, Natural/metabolism , Signal Transduction , Transcription Factors/metabolism , COVID-19 , DNA-Binding Proteins/genetics , Epithelial Cells/immunology , High Mobility Group Proteins/genetics , Humans , Killer Cells, Natural/immunology , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , SARS-CoV-2 , Transcriptional Elongation Factors/genetics , Zika Virus/metabolism , Zika Virus Infection
4.
Structure ; 30(9): 1224-1232.e5, 2022 09 01.
Article in English | MEDLINE | ID: covidwho-1895449

ABSTRACT

Emerging new variants of SARS-CoV-2 and inevitable acquired drug resistance call for the continued search of new pharmacological targets to fight the potentially fatal infection. Here, we describe the mechanisms by which the E protein of SARS-CoV-2 hijacks the human transcriptional regulator BRD4. We found that SARS-CoV-2 E is acetylated in vivo and co-immunoprecipitates with BRD4 in human cells. Bromodomains (BDs) of BRD4 bind to the C-terminus of the E protein, acetylated by human acetyltransferase p300, whereas the ET domain of BRD4 recognizes the unmodified motif of the E protein. Inhibitors of BRD4 BDs, JQ1 or OTX015, decrease SARS-CoV-2 infectivity in lung bronchial epithelial cells, indicating that the acetyllysine binding function of BDs is necessary for the virus fitness and that BRD4 represents a potential anti-COVID-19 target. Our findings provide insight into molecular mechanisms that contribute to SARS-CoV-2 pathogenesis and shed light on a new strategy to block SARS-CoV-2 infection.


Subject(s)
COVID-19 , Cell Cycle Proteins/metabolism , Coronavirus Envelope Proteins/metabolism , SARS-CoV-2/physiology , Transcription Factors/metabolism , COVID-19/virology , Humans , Nuclear Proteins/metabolism , Protein Binding , Protein Domains
5.
Biomed Pharmacother ; 152: 113230, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1881709

ABSTRACT

BACKGROUND: Bromodomain and extraterminal proteins (BETs) are more than just epigenetic regulators of transcription. Here we highlight a new role for the BET protein BRD4 in the maintenance of higher order chromatin structure at Topologically Associating Domain Boundaries (TADBs). BD2-selective and pan (non-selective) BET inhibitors (BETi) differentially support chromatin structure, selectively affecting transcription and cell viability. METHODS: Using RNA-seq and BRD4 ChIP-seq, the differential effect of BETi treatment on the transcriptome and BRD4 chromatin occupancy of human aortic endothelial cells from diabetic patients (dHAECs) stimulated with TNFα was evaluated. Chromatin decondensation and DNA fragmentation was assessed by immunofluorescence imaging and quantification. Key dHAEC findings were verified in proliferating monocyte-like THP-1 cells using real time-PCR, BRD4 co-immunoprecipitation studies, western blots, proliferation and apoptosis assays. FINDINGS: We discovered that 1) BRD4 co-localizes with Ying-Yang 1 (YY1) at TADBs, critical chromatin structure complexes proximal to many DNA repair genes. 2) BD2-selective BETi enrich BRD4/YY1 associations, while pan-BETi do not. 3) Failure to support chromatin structures through BRD4/YY1 enrichment inhibits DNA repair gene transcription, which induces DNA damage responses, and causes widespread chromatin decondensation, DNA fragmentation, and apoptosis. 4) BD2-selective BETi maintain high order chromatin structure and cell viability, while reducing deleterious pro-inflammatory transcription. INTERPRETATION: BRD4 plays a previously unrecognized role at TADBs. BETi differentially impact TADB stability. Our results provide translational insight for the development of BETi as therapeutics for a range of diseases including CVD, chronic kidney disease, cancer, and COVID-19.


Subject(s)
COVID-19 , Transcription Factors , Cell Cycle Proteins/metabolism , Chromatin , Endothelial Cells/metabolism , Epigenesis, Genetic , Humans , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Transcription Factors/metabolism
6.
Epigenomics ; 14(3): 153-162, 2022 02.
Article in English | MEDLINE | ID: covidwho-1622527

ABSTRACT

Smoking could predispose individuals to a more severe COVID-19 by upregulating a particular gene known as mdig, which is mediated through a number of well-known histone modifications. Smoking might regulate the transcription-activating H3K4me3 mark, along with the transcription-repressing H3K9me3 and H3K27me3 marks, in a way to favor SARS-CoV-2 entry by enhancing the expression of ACE2, NRP1 and NRP2, AT1R, CTSD and CTSL, PGE2 receptors 2-4, SLC6A20 and IL-6, all of which interact either directly or indirectly with important receptors, facilitating viral entry in COVID-19.


Lay abstract The role of smoking in development of several respiratory diseases has been clearly established. A significant proportion of these deleterious effects is mediated through epigenetic mechanisms, particularly histone modifications. Recent evidence indicates that smoking induces the expression of a mediator known as mdig, which in turn alters the transcription of several key proteins that have been implicated in development of COVID-19.


Subject(s)
COVID-19/genetics , Dioxygenases/genetics , Epigenesis, Genetic , Histone Demethylases/genetics , Histones/genetics , Nuclear Proteins/genetics , Protein Processing, Post-Translational , Smoking/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , COVID-19/metabolism , COVID-19/virology , Cathepsin D/genetics , Cathepsin D/metabolism , Cathepsin L/genetics , Cathepsin L/metabolism , Dioxygenases/metabolism , Histone Demethylases/metabolism , Histones/metabolism , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Methylation , Neuropilin-1/genetics , Neuropilin-1/metabolism , Neuropilin-2/genetics , Neuropilin-2/metabolism , Nuclear Proteins/metabolism , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptors, Prostaglandin E/genetics , Receptors, Prostaglandin E/metabolism , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Smoking/metabolism , Smoking/pathology , Virus Internalization
7.
Nat Struct Mol Biol ; 28(7): 614-625, 2021 07.
Article in English | MEDLINE | ID: covidwho-1550333

ABSTRACT

p97 processes ubiquitinated substrates and plays a central role in cellular protein homeostasis. Here, we report a series of cryo-EM structures of the substrate-engaged human p97 complex with resolutions ranging from 2.9 to 3.8 Å that captured 'power-stroke'-like motions of both the D1 and D2 ATPase rings of p97. A key feature of these structures is the critical conformational changes of the intersubunit signaling (ISS) motifs, which tighten the binding of nucleotides and neighboring subunits and contribute to the spiral staircase conformation of the D1 and D2 rings. In addition, we determined the cryo-EM structure of human p97 in complex with NMS-873, a potent p97 inhibitor, at a resolution of 2.4 Å. The structures showed that NMS-873 binds at a cryptic groove in the D2 domain and interacts with the ISS motif, preventing its conformational change and thus blocking substrate translocation allosterically.


Subject(s)
Adenosine Triphosphate/chemistry , Protein Folding , Proteostasis/physiology , Signal Transduction/physiology , Valosin Containing Protein/metabolism , Acetanilides/pharmacology , Animals , Benzothiazoles/pharmacology , Cryoelectron Microscopy , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum-Associated Degradation/physiology , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Nuclear Proteins/metabolism , Proteasome Endopeptidase Complex/metabolism , Protein Conformation , Ubiquitinated Proteins/metabolism , Valosin Containing Protein/antagonists & inhibitors
8.
Viruses ; 13(9)2021 09 21.
Article in English | MEDLINE | ID: covidwho-1473721

ABSTRACT

Viruses are obligate intracellular parasites that are dependent on host factors for their replication. One such host protein, p97 or the valosin-containing protein (VCP), is a highly conserved AAA ATPase that facilitates replication of diverse RNA- and DNA-containing viruses. The wide range of cellular functions attributed to this ATPase is consistent with its participation in multiple steps of the virus life cycle from entry and uncoating to viral egress. Studies of VCP/p97 interactions with viruses will provide important information about host processes and cell biology, but also viral strategies that take advantage of these host functions. The critical role of p97 in viral replication might be exploited as a target for development of pan-antiviral drugs that exceed the capability of virus-specific vaccines or therapeutics.


Subject(s)
Adenosine Triphosphatases/metabolism , Nuclear Proteins/metabolism , Valosin Containing Protein/metabolism , Virus Diseases/virology , Virus Replication , Viruses/metabolism , Adenosine Triphosphatases/chemistry , Endoplasmic Reticulum-Associated Degradation , Genome, Viral/genetics , Host-Pathogen Interactions , Humans , Nuclear Proteins/chemistry , Valosin Containing Protein/chemistry , Virus Diseases/immunology , Virus Internalization
9.
Microbiol Spectr ; 9(2): e0090821, 2021 10 31.
Article in English | MEDLINE | ID: covidwho-1452921

ABSTRACT

Emerging coronaviruses (CoVs) can cause severe diseases in humans and animals, and, as of yet, none of the currently available broad-spectrum drugs or vaccines can effectively control these diseases. Host antiviral proteins play an important role in inhibiting viral proliferation. One of the isoforms of cytoplasmic poly(A)-binding protein (PABP), PABPC4, is an RNA-processing protein, which plays an important role in promoting gene expression by enhancing translation and mRNA stability. However, its function in viruses remains poorly understood. Here, we report that the host protein, PABPC4, could be regulated by transcription factor SP1 and broadly inhibits the replication of CoVs, covering four genera (Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus) of the Coronaviridae family by targeting the nucleocapsid (N) protein through the autophagosomes for degradation. PABPC4 recruited the E3 ubiquitin ligase MARCH8/MARCHF8 to the N protein for ubiquitination. Ubiquitinated N protein was recognized by the cargo receptor NDP52/CALCOCO2, which delivered it to the autolysosomes for degradation, resulting in impaired viral proliferation. In addition to regulating gene expression, these data demonstrate a novel antiviral function of PABPC4, which broadly suppresses CoVs by degrading the N protein via the selective autophagy pathway. This study will shed light on the development of broad anticoronaviral therapies. IMPORTANCE Emerging coronaviruses (CoVs) can cause severe diseases in humans and animals, but none of the currently available drugs or vaccines can effectively control these diseases. During viral infection, the host will activate the interferon (IFN) signaling pathways and host restriction factors in maintaining the innate antiviral responses and suppressing viral replication. This study demonstrated that the host protein, PABPC4, interacts with the nucleocapsid (N) proteins from eight CoVs covering four genera (Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus) of the Coronaviridae family. PABPC4 could be regulated by SP1 and broadly inhibits the replication of CoVs by targeting the nucleocapsid (N) protein through the autophagosomes for degradation. This study significantly increases our understanding of the novel host restriction factor PABPC4 against CoV replication and will help develop novel antiviral strategies.


Subject(s)
Autophagy/physiology , Blood Proteins/metabolism , Coronavirus Nucleocapsid Proteins/metabolism , Coronavirus/growth & development , Poly(A)-Binding Proteins/metabolism , Virus Replication/physiology , Animals , Cell Line , Chlorocebus aethiops , HEK293 Cells , Humans , Infectious bronchitis virus/growth & development , Murine hepatitis virus/growth & development , Nuclear Proteins/metabolism , Porcine epidemic diarrhea virus/growth & development , Proteolysis , Sp1 Transcription Factor/metabolism , Swine , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Vero Cells
10.
Nat Commun ; 12(1): 4918, 2021 08 13.
Article in English | MEDLINE | ID: covidwho-1397870

ABSTRACT

Ribosomal RNA genes (rDNA) are highly unstable and susceptible to rearrangement due to their repetitive nature and active transcriptional status. Sequestration of rDNA in the nucleolus suppresses uncontrolled recombination. However, broken repeats must be first released to the nucleoplasm to allow repair by homologous recombination. Nucleolar release of broken rDNA repeats is conserved from yeast to humans, but the underlying molecular mechanisms are currently unknown. Here we show that DNA damage induces phosphorylation of the CLIP-cohibin complex, releasing membrane-tethered rDNA from the nucleolus in Saccharomyces cerevisiae. Downstream of phosphorylation, SUMOylation of CLIP-cohibin is recognized by Ufd1 via its SUMO-interacting motif, which targets the complex for disassembly through the Cdc48/p97 chaperone. Consistent with a conserved mechanism, UFD1L depletion in human cells impairs rDNA release. The dynamic and regulated assembly and disassembly of the rDNA-tethering complex is therefore a key determinant of nucleolar rDNA release and genome integrity.


Subject(s)
Cell Nucleolus/genetics , DNA Repair , DNA, Ribosomal/genetics , Saccharomyces cerevisiae Proteins/genetics , Small Ubiquitin-Related Modifier Proteins/genetics , Valosin Containing Protein/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Nucleolus/metabolism , DNA Damage , DNA, Ribosomal/metabolism , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mutation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Phosphorylation , Protein Binding , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Small Ubiquitin-Related Modifier Proteins/metabolism , Sumoylation , Two-Hybrid System Techniques , Valosin Containing Protein/metabolism
11.
Int J Mol Sci ; 22(3)2021 Jan 22.
Article in English | MEDLINE | ID: covidwho-1389387

ABSTRACT

In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for a long time as the only transcriptional regulator. More recently, it was found that its closest homolog, NLRC5 (NLR protein caspase activation and recruitment domain (CARD)-containing 5), is a regulator of MHC-I gene expression. Both act as non-DNA-binding activators through multiple protein-protein interactions with an MHC enhanceosome complex that binds cooperatively to a highly conserved combinatorial cis-acting module. Thus, the regulation of MHC-II expression is regulated largely through the differential expression of CIITA. In addition to the well-defined role of CIITA in MHC-II GENE regulation, we will discuss several other aspects of CIITA functions, such as its role in cancer, its role as a viral restriction element contributing to intrinsic immunity, and lastly, its very recently discovered role as an inhibitor of Ebola and SARS-Cov-2 virus replication. We will briefly touch upon the recently discovered role of NLRP3 as a transcriptional regulator, which suggests that transcriptional regulation is, after all, not such an unusual feature for NLR proteins.


Subject(s)
Genes, MHC Class II , NLR Proteins/metabolism , Nuclear Proteins/metabolism , Trans-Activators/metabolism , Animals , COVID-19/genetics , COVID-19/metabolism , Ebolavirus/physiology , Gene Expression Regulation , Hemorrhagic Fever, Ebola/genetics , Hemorrhagic Fever, Ebola/metabolism , Humans , NLR Proteins/genetics , Neoplasms/genetics , Neoplasms/metabolism , Nuclear Proteins/genetics , Protein Interaction Maps , SARS-CoV-2/physiology , Trans-Activators/genetics , Virus Replication
12.
Theranostics ; 11(16): 7970-7983, 2021.
Article in English | MEDLINE | ID: covidwho-1337804

ABSTRACT

The novel ß-coronavirus, SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), has infected more than 177 million people and resulted in 3.84 million death worldwide. Recent epidemiological studies suggested that some environmental factors, such as air pollution, might be the important contributors to the mortality of COVID-19. However, how environmental exposure enhances the severity of COVID-19 remains to be fully understood. In the present report, we provided evidence showing that mdig, a previously reported environmentally-induced oncogene that antagonizes repressive trimethylation of histone proteins, is an important regulator for SARS-CoV-2 receptors neuropilin-1 (NRP1) and NRP2, cathepsins, glycan metabolism and inflammation, key determinants for viral infection and cytokine storm of the patients. Depletion of mdig in bronchial epithelial cells by CRISPR-Cas-9 gene editing resulted in a decreased expression of NRP1, NRP2, cathepsins, and genes involved in protein glycosylation and inflammation, largely due to a substantial enrichment of lysine 9 and/or lysine 27 trimethylation of histone H3 (H3K9me3/H3K27me3) on these genes as determined by ChIP-seq. Meanwhile, we also validated that environmental factor arsenic is able to induce mdig, NRP1 and NRP2, and genetic disruption of mdig lowered expression of NRP1 and NRP2. Furthermore, mdig may coordinate with the Neanderthal variants linked to an elevated mortality of COVID-19. These data, thus, suggest that mdig is a key mediator for the severity of COVID-19 in response to environmental exposure and targeting mdig may be the one of the effective strategies in ameliorating the symptom and reducing the mortality of COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Dioxygenases/metabolism , Histone Demethylases/metabolism , Neuropilin-1/metabolism , Nuclear Proteins/metabolism , Polysaccharides/metabolism , SARS-CoV-2/metabolism , Alveolar Epithelial Cells/metabolism , Animals , COVID-19/epidemiology , Cathepsins/metabolism , Cell Line , Cells, Cultured , Dioxygenases/biosynthesis , Dioxygenases/genetics , Environmental Exposure , Histone Demethylases/biosynthesis , Histone Demethylases/genetics , Histones/metabolism , Humans , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , Pandemics , Rats , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism
13.
Genes Dev ; 35(15-16): 1123-1141, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1322683

ABSTRACT

Spliceosomal small nuclear RNAs (snRNAs) are modified by small Cajal body (CB)-specific ribonucleoproteins (scaRNPs) to ensure snRNP biogenesis and pre-mRNA splicing. However, the function and subcellular site of snRNA modification are largely unknown. We show that CB localization of the protein Nopp140 is essential for concentration of scaRNPs in that nuclear condensate; and that phosphorylation by casein kinase 2 (CK2) at ∼80 serines targets Nopp140 to CBs. Transiting through CBs, snRNAs are apparently modified by scaRNPs. Indeed, Nopp140 knockdown-mediated release of scaRNPs from CBs severely compromises 2'-O-methylation of spliceosomal snRNAs, identifying CBs as the site of scaRNP catalysis. Additionally, alternative splicing patterns change indicating that these modifications in U1, U2, U5, and U12 snRNAs safeguard splicing fidelity. Given the importance of CK2 in this pathway, compromised splicing could underlie the mode of action of small molecule CK2 inhibitors currently considered for therapy in cholangiocarcinoma, hematological malignancies, and COVID-19.


Subject(s)
Interstitial Cells of Cajal/metabolism , Methylation , Nuclear Proteins/metabolism , Phosphoproteins/metabolism , RNA Splicing , RNA, Small Nuclear/metabolism , COVID-19/drug therapy , Casein Kinase II/antagonists & inhibitors , Casein Kinase II/metabolism , Cholangiocarcinoma/drug therapy , Hematologic Neoplasms/drug therapy , Humans , Phosphorylation , RNA, Small Nuclear/chemistry , Ribonucleoproteins/metabolism , Spliceosomes/genetics
14.
Cell Host Microbe ; 29(8): 1277-1293.e6, 2021 Aug 11.
Article in English | MEDLINE | ID: covidwho-1293647

ABSTRACT

Immune deactivation of phagocytes is a central event in the pathogenesis of sepsis. Herein, we identify a master regulatory role of IL-6 signaling on LC3-associated phagocytosis (LAP) and reveal that uncoupling of these two processes during sepsis induces immunoparalysis in monocytes/macrophages. In particular, we demonstrate that activation of LAP by the human fungal pathogen Aspergillus fumigatus depends on ERK1/2-mediated phosphorylation of p47phox subunit of NADPH oxidase. Physiologically, autocrine IL-6/JAK2/Ninein axis orchestrates microtubule organization and dynamics regulating ERK recruitment to the phagosome and LC3+ phagosome (LAPosome) formation. In sepsis, loss of IL-6 signaling specifically abrogates microtubule-mediated trafficking of ERK, leading to defective activation of LAP and impaired killing of bacterial and fungal pathogens by monocytes/macrophages, which can be selectively restored by IL-6 supplementation. Our work uncovers a molecular pathway linking IL-6 signaling with LAP and provides insight into the mechanisms underlying immunoparalysis in sepsis.


Subject(s)
Interleukin-6/metabolism , Microtubule-Associated Proteins/metabolism , Phagocytosis/immunology , Signal Transduction , Aspergillus fumigatus/metabolism , Cytokines/metabolism , Cytoskeletal Proteins/metabolism , Humans , Janus Kinase 2/metabolism , Macrophages , Monocytes , Nuclear Proteins/metabolism , Phagocytes , Phagocytosis/physiology , Sepsis/metabolism
15.
Viruses ; 12(11)2020 11 18.
Article in English | MEDLINE | ID: covidwho-940255

ABSTRACT

The zinc finger proteins make up a significant part of the proteome and perform a huge variety of functions in the cell. The CCCH-type zinc finger proteins have gained attention due to their unusual ability to interact with RNA and thereby control different steps of RNA metabolism. Since virus infections interfere with RNA metabolism, dynamic changes in the CCCH-type zinc finger proteins and virus replication are expected to happen. In the present review, we will discuss how three CCCH-type zinc finger proteins, ZC3H11A, MKRN1, and U2AF1, interfere with human adenovirus replication. We will summarize the functions of these three cellular proteins and focus on their potential pro- or anti-viral activities during a lytic human adenovirus infection.


Subject(s)
Adenoviridae/physiology , Adenovirus Infections, Human/virology , Host Microbial Interactions , RNA-Binding Proteins/genetics , Zinc Fingers/genetics , Humans , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , RNA-Binding Proteins/metabolism , Ribonucleoproteins/genetics , Ribonucleoproteins/metabolism , Splicing Factor U2AF/genetics , Splicing Factor U2AF/metabolism , Virus Replication
16.
Mol Cell Endocrinol ; 515: 110917, 2020 09 15.
Article in English | MEDLINE | ID: covidwho-661768

ABSTRACT

Obesity patients are more susceptible to develop COVID-19 severe outcome due to the role of angiotensin-converting enzyme 2 (ACE2) in the viral infection. ACE2 is regulated in the human cells by different genes associated with increased (TLR3, HAT1, HDAC2, KDM5B, SIRT1, RAB1A, FURIN and ADAM10) or decreased (TRIB3) virus replication. RNA-seq data revealed 14857 genes expressed in human subcutaneous adipocytes, including genes mentioned above. Irisin treatment increased by 3-fold the levels of TRIB3 transcript and decreased the levels of other genes. The decrease in FURIN and ADAM10 expression enriched diverse biological processes, including extracellular structure organization. Our results, in human subcutaneous adipocytes cell culture, indicate a positive effect of irisin on the expression of multiple genes related to viral infection by SARS-CoV-2; furthermore, translatable for other tissues and organs targeted by the novel coronavirus and present, thus, promising approaches for the treatment of COVID-19 infection as therapeutic strategy to decrease ACE2 regulatory genes.


Subject(s)
Adipocytes/drug effects , Fibronectins/pharmacology , Gene Expression Regulation/drug effects , ADAM10 Protein/genetics , ADAM10 Protein/metabolism , Adipocytes/cytology , Adipocytes/metabolism , Amyloid Precursor Protein Secretases/genetics , Amyloid Precursor Protein Secretases/metabolism , Angiotensin-Converting Enzyme 2 , Betacoronavirus/genetics , Betacoronavirus/metabolism , COVID-19 , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cells, Cultured , Coronavirus Infections/virology , Fibronectins/genetics , Fibronectins/metabolism , Furin/genetics , Furin/metabolism , Gene Ontology , Histone Acetyltransferases/genetics , Histone Acetyltransferases/metabolism , Histone Deacetylase 2/genetics , Histone Deacetylase 2/metabolism , Humans , Jumonji Domain-Containing Histone Demethylases/genetics , Jumonji Domain-Containing Histone Demethylases/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Models, Biological , Molecular Sequence Annotation , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Obesity/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/virology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , SARS-CoV-2 , Signal Transduction , Sirtuin 1/genetics , Sirtuin 1/metabolism , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/metabolism , rab1 GTP-Binding Proteins/genetics , rab1 GTP-Binding Proteins/metabolism
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