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Proteome wide screening for ubiquitination, ISGylation and NEDDylation sites in wildtype and ISG15 knockout mouse hearts after transverse aortic constriction

ABSTRACT: Hearts(left ventricles) were harvested from control wildtype and ISG15 knockout mice and wildtype and ISG15 knockout mice 4 weeks after pressure overload induced by transverse aortic constriction. Nano LC-MS/MS analysis was performedon left ventricle tissue following protein extraction, trypsin digestion, peptide desalting, anti K-e-GG enrichment.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Ventricular Cardiac Muscle Cell, T Cell, Endothelial Cell, Fibroblast, Macrophage

DISEASE(S): Systolic Heart Failure,Heart Failure

SUBMITTER: Andrew Advani

LAB HEAD: Andrew Advani

PROVIDER: PXD032267 | Pride | 2023-05-10

REPOSITORIES: Pride

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Pressure overload induces ISG15 to facilitate adverse ventricular remodeling and promote heart failure.

Yerra Veera Ganesh VG Batchu Sri Nagarjun SN Kaur Harmandeep H Kabir M D Golam MDG Liu Youan Y Advani Suzanne L SL Tran Duc Tin DT Sadeghian Shadi S Sedrak Phelopater P Billia Filio F Kuzmanov Uros U Gramolini Anthony O AO Qasrawi Deema O DO Petrotchenko Evgeniy V EV Borchers Christoph H CH Connelly Kim A KA Advani Andrew A

The Journal of clinical investigation 20230501 9

Inflammation promotes adverse ventricular remodeling, a common antecedent of heart failure. Here, we set out to determine how inflammatory cells affect cardiomyocytes in the remodeling heart. Pathogenic cardiac macrophages induced an IFN response in cardiomyocytes, characterized by upregulation of the ubiquitin-like protein IFN-stimulated gene 15 (ISG15), which posttranslationally modifies its targets through a process termed ISGylation. Cardiac ISG15 is controlled by type I IFN signaling, and I ...[more]

PMID: 37115698

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Metabolomic analysis in wildtype and Isg15 knockout mice after sham or transverse aortic constriction surgery

Project description:Left ventricular tissues were isolated from wildtype and Isg15 knockout mice 8 weeks after sham or transverse aortic constriction and the metabolomic differences were compared.

2023-01-07 | ST002437 | MetabolomicsWorkbench

ISG15 in regulation of interferon responses

Project description:We assessed how lack of ISG15 influences the levels of transcripts after IFNa stimulation. Expression data from ISG15 deficient patients (P1, P2, P3) and control (C1, C6, C16) hTert fibroblasts

2014-12-01 | GSE60359 | GEO

ISG15 counteracts Listeria monocytogenes infection

Project description:ISG15 counteracts Listeria monocytogenes infection

| PRJEB9655 | ENA

Proteomics-based identification of ISG15 modification sites during Listeria monocytogenes infection

Project description:ISG15 is an interferon-stimulated, ubiquitin-like protein, with anti-viral and anti-bacterial activity, however its precise mechanism of action during viral or bacterial infection remains elusive. We previously found that ISG15 restricts Listeria infection both in vitro and in vivo and identified ISGylated proteins that could be responsible for the protective effect. Here, we endeavored to map the in vivo ISGylome following Listeria infection to mechanistically elucidate the function of ISG15 in host defense. To do so we combined a genetic approach employing a murine model of deregulated ISGylation with quantitative proteomics of immune-enriched endogenous ISG15 modification sites. In this way, we mapped 930 ISG15 sites in 438 proteins. In addition, we also quantified protein level changes in the host proteome following infection. Gene ontology analysis revealed that ISGylated proteins were mostly enriched in proteins which alter cellular metabolic processes, including four upstream modulators of the catabolic and antibacterial pathway of autophagy. Structural analysis further revealed that a number of ISG15 modifications can occur at catalytic sites or dimerization interfaces of enzymes. Finally, we showed that animals and cells with deregulated ISGylation have increased infection-induced autophagy through the modification of mTOR, WIPI2, and AMBRA1. Taken together, these findings ascribe a putative role of ISGylation to temporarily reprogram organismal metabolism following infection through direct modification of a variety of enzymes in the liver.

2019-11-28 | PXD011513 | Pride

Network analysis identifies proinflammatory plasma cell polarization for secretion of ISG15 in human autoimmunity

Project description:Plasma cells (PCs) as effectors of humoral immunity produce immunoglobulins to match pathogenic insult. However, emerging data suggests more diverse roles for PCs as regulators of immune and inflammatory responses via secretion of factors other than immunoglobulins. The extent to which such responses are pre-programmed in B-lineage cells or can be induced in PCs by the microenvironment is unknown. Here we dissect the impact of IFNs on the regulatory networks of human plasma cells. We show that core PC programs are unaffected, while PCs respond to IFNs with distinctive transcriptional responses. The ISG15-system emerges as a major transcriptional output induced in a sustained fashion by IFN-Î± in PCs and linked both to intracellular conjugation and ISG15 secretion. This leads to the identification of ISG15-secreting plasmablasts/PCs in patients with active SLE. Thus ISG15-secreting PCs represent a distinct pro-inflammatory PC subset providing an immunoglobulin-independent mechanism of PC action in human autoimmunity B-cells were isolated from the peripheral blood of three adult donors and differentiated in vitro (see individual samples for culture conditions)

2016-07-22 | E-GEOD-75007 | biostudies-arrayexpress

ISG15 counteracts Listeria monocytogenes infection

Project description:ISG15 is primarily documented as an interferon-stimulated, ubiquitin-like protein (ubl), which has anti-viral activity. Although ISG15 was the founding member of the ubl protein family, very little is known about its function. We have found that ISG15 expression in non-phagocytic cells is dramatically induced upon Listeria infection and that surprisingly this induction can be Type I Interferon independent. Listeria-mediated ISG15 induction depends on the cytosolic surveillance pathway, which senses bacterial DNA and signals through STING, TBK1, IRF3 and IRF7. Most importantly, we observed that ISG15 expression restricts Listeria infection both in vitro and in vivo. We then made use of Stable Isotope Labeling in tissue culture (SILAC) to identify the ISGylated proteins that could be responsible for the ISG15-mediated protective effect. Our SILAC analysis revealed that overexpression of ISG15 leads to a striking ISGylation of integral membrane proteins of the endoplasmic reticulum and Golgi apparatus, which correlates with increased canonical secretion of cytokines. Taken together, our data reveal a previously uncharacterized signaling pathway that restricts Listeria infection and acts via ISGylation, reinforcing the view that ISG15 is a key component of the innate immune arsenal of the mammalian host.

2017-03-29 | MSV000080750 | MassIVE

ISG15 counteracts Listeria monocytogenes infection

2015-07-24 | PXD001805 | Pride

USP16 is an ISG15 cross-reactive deubiquitinase targeting a subset of metabolic pathway-related proteins

Project description:The ubiquitin-like modifier ISG15 can modulate host and viral proteins to restrict viral and microbial infections, and act as a cytokine. Its expression and conjugation are strongly up-regulated by type I interferons. Here we identify the deubiquitinating enzyme USP16 as an ISG15 cross-reactive protease. Ubiquitin-specific protease 16 (USP16) was found to react with an ISG15 activity-based probe in pull-down experiments using chronic myeloid leukaemia-derived human cells (HAP1). Supporting this finding, recombinant USP16 cleaved pro-ISG15 and ISG15 iso-peptide linked model substrates in vitro, as well as ISGylated substrates present in cell lysates. Moreover, the interferon-induced stimulation of ISGylation in human HAP1 cells was increased by knockdown or knockout of USP16. Depletion of USP16 did not affect interferon signaling, and interferon treatment did not affect USP16 expression or enzymatic activity either. A USP16-dependent ISG15 interactome was established by anti-ISG15 immunoprecipitation mass spectrometry (IP-MS), which indicated that the deISGylating function of USP16 may regulate metabolic pathways involving GOT1, ALDOA, SOD1 and MDH1, all of which were further confirmed to be deISGylated by USP16 in HEK293T cells. Together, our results indicate that USP16 may contribute to regulating the ISGylation status of a subset of proteins related to metabolism during type I interferon responses.

2023-11-17 | PXD043553 | Pride

Network analysis identifies proinflammatory plasma cell polarization for secretion of ISG15 in human autoimmunity

Project description:Plasma cells (PCs) as effectors of humoral immunity produce immunoglobulins to match pathogenic insult. However, emerging data suggests more diverse roles for PCs as regulators of immune and inflammatory responses via secretion of factors other than immunoglobulins. The extent to which such responses are pre-programmed in B-lineage cells or can be induced in PCs by the microenvironment is unknown. Here we dissect the impact of IFNs on the regulatory networks of human plasma cells. We show that core PC programs are unaffected, while PCs respond to IFNs with distinctive transcriptional responses. The ISG15-system emerges as a major transcriptional output induced in a sustained fashion by IFN-α in PCs and linked both to intracellular conjugation and ISG15 secretion. This leads to the identification of ISG15-secreting plasmablasts/PCs in patients with active SLE. Thus ISG15-secreting PCs represent a distinct pro-inflammatory PC subset providing an immunoglobulin-independent mechanism of PC action in human autoimmunity

2016-07-22 | GSE75007 | GEO

The Innate Immune Factor IRF3 Reduces Adipose Thermogenesis via ISG15-mediated Reprogramming of Cellular Metabolism

Project description:Purpose: Interferon regulatory factor 3 (IRF3) is activated by pro-inflammatory cytokines, but its role in regulating adaptive thermogenesis and energy expenditure remains unclear. Here, we report that IRF3 as a negative transcription regulator of adaptive thermogenesis. Adipocyte-specific IRF3 knockout (FI3KO) attenuates HFD-induced obesity by increasing energy expenditure; further studies show that IRF3 suppresses adaptive thermogenesis through ISG15-mediated inhibition of glycolysis in adipocytes. Conversely, overexpression of IRF3 in adipocytes causes reduced thermogenesis gene expression, energy expenditure, and more persistent to HFD-induced obesity. Moreover, Isg15-/- increases adipose thermogenesis and protects mice from HFD-induced obesity and glucose intolerance. Taken together, these data indicate that IRF3 as a transcriptional regulator connecting between inflammatory signaling pathway and energy homeostasis Methods: primary adipocyte mRNA profiles of 8-week-old wild-type (WT) and FI3OE mice were generated by deep sequencing. The sequence reads that passed quality filters were analyzed at the transcript isoform level. qRT–PCR validation was performed using RT-PCR. Conclusions: Our study represents the first detailed analysis of adipocyte transcriptomes from WT and FI3OE iWAT, with biologic replicates, generated by RNA-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles. Our results show that Irf3 adipocyte-speficic overrxpression markedly increases the expression of Isg15 and Herc6, which play important role in regulation of glycolysis.

2020-07-24 | GSE155019 | GEO

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