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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):

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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Dataset's files

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			Action	DRS
	GlyGly__K_Sites.txt	Txt
	KO_Control1.raw	Raw
	KO_Control2.raw	Raw
	KO_Control3.raw	Raw
	KO_TAC1.raw	Raw

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1 - 5 of 27

Publications

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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ISGylation of H2AX retains MDC1 and facilitates homologous recombination repair causing radioresistance in esophageal adenocarcinoma

Project description:High expression of interferon-stimulated gene 15 (ISG15) has been associated with poor survival in patients with esophageal adenocarcinoma (EAC). Like ubiquitin, ISG15 utilizes its C-terminal LRGG motif to post-translationally modify target proteins through a process called ISGylation, thereby influencing their stability, function, and interaction networks. Given ISG15’s role in the replication stress response, we hypothesized that it may also contribute to DNA repair mechanisms. We found that ISG15 is upregulated following ionizing radiation (IR), and its knockdown disrupts the IR-induced G2/M checkpoint, leading to increased radiosensitivity in EAC cells. In synchronized cells, ISG15 expression peaks during the S/G2 phases. Knockdown of ISG15 impairs homologous recombination repair (HRR) with compensatory upregulation of non-homologous end joining (NHEJ). Similarly, cells expressing an ISGylation-defective ISG15LRAA mutant exhibit reduced HRR activity and elevated NHEJ, highlighting the critical role of ISGylation in the DNA damage response (DDR). Further investigation revealed that IR-induced ISG15 modifies H2AX at lysine 120 (K120). Overexpression of an H2AXK120R mutant in EAC cells resulted in diminished MDC1 retention at DNA damage sites, mirroring the phenotype observed with ISG15 knockdown. Additionally, depletion of ISG15 delays RAD51 foci formation at damage sites. Using a tissue microarray of chemoresistant EAC patients, we observed that ISG15 is expressed in almost all cases and that along with high RAD51 expression correlates with poorer prognosis in node-positive patients. Collectively, we identify H2AX as a novel substrate of IR-induced ISGylation, which facilitates efficient recruitment and retention of downstream HRR proteins and may contribute to radioresistance in EAC.

2026-04-27 | PXD071548 | Pride

Ubiquitinome of Plasmodium yoelii lines NSS and NSR

Project description:Ubiquitinome profiling of blood stages of Plasmodium yoelii lines NSS and NSR

2024-02-04 | PXD047782 | Pride

NFkB signaling and ISGylation associated with BRCA1-mutated fallopian tube epithelium

Project description:Germline BRCA1 or BRCA2 mutations (mtBRCA1 and mtBRCA2) dramatically increase risk for high-grade serous ovarian cancer (HGSOC), the most commonly diagnosed histotype. Other risk factors for this cancer, which originates primarily in the distal fallopian tube epithelium (FTE), implicate ovulation. To test whether mtBRCA1 or mtBRCA2 FTE cells respond differently to peri-ovulatory follicular fluid (FF) exposure than control patient FTE, gene expression profiles from primary FTE cultures were compared at baseline, 24h after FF exposure, and 24h after FF replacement with culture medium. Hierarchical clustering revealed both FF exposure and BRCA mutation status affect gene expression, with BRCA1 mutation having the greatest impact. Analysis revealed increased NFκB and EGFR signaling at baseline, with increased interferon signaling after recovery from FF exposure in mtBRCA1 samples. Inhibition of EGFR signaling and ISGylation by increased BRCA1 expression was verified in an immortalized FTE cell line, OE-E6/E7, stably transfected with BRCA1. Suppression of ISG15 and ISGylated protein levels by BRCA1 expression was found to be mediated by decreased NFκB signaling and was transiently suppressed by FF exposure. This study demonstrates increased NFκB signaling associated with decreased BRCA1 expression resulting in increased ISG15 and ISGylation following FF exposure, which could represent potential targets for chemoprevention.

2018-05-31 | GSE98699 | GEO

Proteomics and tracer metabolomics link GAPDH ISGylation to glycolytic control

Project description:<p>Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) has been implicated in the regulation of central carbon metabolism, but conflicting findings across experimental systems have limited mechanistic insight. Here, we applied a multi-omics approach in cells ectopically expressing the ISGylation machinery independent of immune stimuli, to generate a systematic view of ISGylation in metabolic control. We found that ISGylation predominantly modifies metabolic proteins, including key glycolytic enzymes, and is associated with suppression of the energy-producing phase of glycolysis. Tracer metabolomics indicated a bottleneck at glyceraldehyde-3-phosphate dehydrogenase (GAPDH), marked by accumulation of its substrate and depletion of downstream metabolites. Functional assays demonstrated that ISGylation directly impairs GAPDH activity, and structural analysis revealed that ISG15 modifications cluster near the active site and dimerization interfaces, critical for enzymatic function. These findings identify GAPDH as a central metabolic checkpoint regulated by ISGylation and uncover a direct post-translational mechanism by which ISG15 controls energy metabolism.</p>

2026-03-02 | MTBLS12619 | MetaboLights

Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas

Project description:Prednisone is anti-inflammatory glucocorticoid (GC), and GC-based therapy is most used combination chemotherapy for treating aggressive B-cell lymphomas. However, there are still gaps in our understanding of specific mechanism of GCâ€™s action for its cytotoxicity. By performing multi-omics approaches, we identified new GR targets and how these targets control the b-cell receptor signaling networks, providing a mechanistic framework upon which to base combination therapies.

2024-05-02 | PXD041891 | Pride

Sex differences in RBM20 cardiomyopathy

Project description:In this study, we investigated potential sex differences in a Rbm20 knockout mouse model. We used RNA sequencing of bulk RNA from the left ventricle of male and female wildtype and Rbm20 knockout mice.

2022-10-27 | GSE216147 | GEO

Heart fibroblasts from Siah-knockout mice in hypoxia

Project description:Heart fibroblasts from wildtype mice and Siah2-/- knockout mice were isolated and cultured. The cells were either left untreated or incubated for 6 hs under hypoxic conditions. One experiment consists of wildtype cells (normoxia/hypoxia) and Siah2 knockout cells (normoxia/hypoxia) = 4 samples. To allow statistical analysis of the data set the experiment was repeated once under identical conditions.

2021-07-01 | GSE154667 | GEO

Proteome-wide identification of ISG15 sites in HeLa cells

Project description:We employed a GlyGly-peptidomics approach to comprehensively map ISG15 modification sites in HeLa cells under three conditions: mock-transfected controls, IFN-induced cells, and cells transfected with the ISGylation machinery. Lysates from wild-type and Isg15 knockout (KO) cells were processed using S-trap, followed by trypsin digestion to generate diglycine-modified peptides. These peptides were enriched via immunoprecipitation and analyzed by LC-MS/MS for identification and quantification. Comparative analysis across conditions and genotypes revealed 671 ISG15 modification sites on 456 distinct proteins, expanding the HeLa ISGylome.

2026-03-02 | PXD065158 | Pride

Transcriptome profiling of left ventricles from Wildtype and KDM5B knockout mice

Project description:Transcriptome profiling of left ventricles from Wildtype and KDM5B knockout mice

| PRJNA809385 | ENA

Hexokinase 2 Exacerbates Mitochondrial Damage, Neuroinflammation, and Lipid accumulation by promoting ACSL4 ISGylation in Sepsis-Associated Encephalopathy

Project description:Metabolic reprogramming is often observed in sepsis-associated encephalopathy (SAE). However, little is known about the aberrant metabolic genes involved in mitochondrial damage, neuroinflammation, and lipid accumulation in microglial cells. Here, we show that hexokinase 2 (HK2) is upregulated and is strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Genetic silencing or pharmacological inhibition of HK2 attenuates mitochondrial damage in vitro. Downregulation of HK2 lowered the NOD-like receptor signaling family pyrin domain containing three activations, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction and activated mammalian target of rapamycin-mediated autophagy. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) during lipid metabolism by interferon-stimulated gene 15 (ISG15). Notably, ISG15 eﬀectively down-regulated the expression of ACSL4 in vitro. Our findings provide new mechanistic insights of HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2.

2025-04-30 | GSE280721 | GEO

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