The in vivo ISGylome links ISG15 to metabolic pathways and autophagy upon Listeria monocytogenes infection

Zhang, Yifeng; Thery, Fabien; Wu, Nicholas C.; Luhmann, Emma; Dussurget, Olivier; Foecke, Mariko H.; Bredow, Clara; Fernández, Daniel; Leandro, Kevin; Beling, Antje; Knobeloch, Klaus Peter; Impens, Francis; Cossart, Pascale; Radoshevich, Lilliana

doi:10.1038/s41467-019-13393-x

Cited by 75 publications

(98 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With respect to immunometabolism, mitochondrial metabolism shows a remarkable sensitivity to chemokine and IFN signaling [95,102]. For example, ISG15 is an interferon-stimulated, ubiquitin-like protein which regulates mitochondrial homeostasis and targets various proteins involved in catabolic autophagy metabolism in the mitochondria (mitophagy) during infection [103,104]. Moreover, mitochondrial changes in immunometabolism (glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism) strongly contribute in (re)shaping immunity and production of neutrophil extracellular traps (NETs) [105][106][107][108].…”

Section: Discussionmentioning

confidence: 99%

Standardized Echinacea purpurea extract primes an IFN specific innate immune monocyte response via JAK1-STAT1 dependent gene expression and epigenetic control of endogenous retroviral sequences

Declerck¹,

Pérez-Novo²,

Grielens³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Herbal remedies of Echinacea purpurea tinctures are widely used today to reduce common cold respiratory tract infections.Methods: A system biology approach involving genomewide transcriptome, epigenome and kinome activity profiles was applied to characterize the immunomodulatory effects of a standardized Echinacea purpurea extract Echinaforce® in THP1 monocytes.Results: Gene expression and DNA methylation analysis revealed activation of innate immunity related antiviral signaling networks, involving IFN, chemotaxis and immunometabolic pathways. Furthermore, phosphopeptide based kinome activity profiling and pharmacological inhibitor experiments with filgotinib confirm a key role for Janus Kinase (JAK)-1 dependent gene expression changes in innate immune signaling. Finally, Echinaforce® treatment induces DNA hypermethylation at intergenic CpG, long/short interspersed nuclear DNA repeat elements (LINE, SINE) or long termininal DNA repeats (LTR). This changes transcription of flanking endogenous retroviral sequences (HERVs), involved in an evolutionary conserved (epi)genomic protective response against viral infections.Conclusions: Altogether, our results suggest that Echinaforce® phytochemicals strengthen antiviral innate immunity by JAK1 responsive gene expression and epigenetic regulation of HERVs in monocytes, which supports its prophylactic use against common cold corona viruses (CoV), Severe Acute Respiratory Syndrome (SARS)-CoV, and new occurring strains such as SARS-CoV-2.

show abstract

Section: Discussionmentioning

confidence: 99%

Standardized Echinacea purpurea extract primes an IFN specific innate immune monocyte response via JAK1-STAT1 dependent gene expression and epigenetic control of endogenous retroviral sequences

Declerck¹,

Pérez-Novo²,

Grielens³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Studying how these genetic alterations alter the ubiquitome in patient samples could prove very informative and indeed lead to more effective forms of therapy. Mouse tissue has been used successfully for K-GG profiling studies [ 20 , 145 ]. However, since the required amount of starting material for performing ubiquitin site profiling studies is relatively high and the cellular material coming from patients is normally low, this has been challenging so far.…”

Section: Translational Ubiquitomicsmentioning

confidence: 99%

Ubiquitomics: An Overview and Future

et al. 2020

View full text Add to dashboard Cite

Covalent attachment of ubiquitin, a small globular polypeptide, to protein substrates is a key post-translational modification that determines the fate, function, and turnover of most cellular proteins. Ubiquitin modification exists as mono- or polyubiquitin chains involving multiple ways how ubiquitin C-termini are connected to lysine, perhaps other amino acid side chains, and N-termini of proteins, often including branching of the ubiquitin chains. Understanding this enormous complexity in protein ubiquitination, the so-called ‘ubiquitin code’, in combination with the ∼1000 enzymes involved in controlling ubiquitin recognition, conjugation, and deconjugation, calls for novel developments in analytical techniques. Here, we review different headways in the field mainly driven by mass spectrometry and chemical biology, referred to as “ubiquitomics”, aiming to understand this system’s biological diversity.

show abstract

“…In this study, authors employed Lys-ε-GG antibody IP in wildtype and ISG15 −/− mice followed by LC tandem MS-MS analysis. Comparison of the datasets allowed to identify and distinguish ISGylated sites from ubiquitin sites in vivo (Zhang et al, 2019). Similar approaches have already been used in several cell systems to identify different post-translational modifications such as, phosphorylation (Rush et al, 2005), ubiquitination (Xu et al, 2010a;Kim et al, 2011), acetylation (Weinert et al, 2011;Kori et al, 2017), methylation and SUMOylation (Impens et al, 2014;Lamoliatte et al, 2017).…”

Section: Identification Of Isg15 Substratesmentioning

confidence: 99%

Strategies to Target ISG15 and USP18 Toward Therapeutic Applications

2020

Self Cite

View full text Add to dashboard Cite

The interferon (IFN)-stimulated gene product 15 (ISG15) represents an ubiquitin-like protein (Ubl), which in a process termed ISGylation can be covalently linked to target substrates via a cascade of E1, E2, and E3 enzymes. Furthermore, ISG15 exerts functions in its free form both, as an intracellular and as a secreted protein. In agreement with its role as a type I IFN effector, most functions of ISG15 and ISGylation are linked to the anti-pathogenic response. However, also key roles in other cellular processes such as protein translation, cytoskeleton dynamics, exosome secretion, autophagy or genome stability and cancer were described. Ubiquitin-specific protease 18 (USP18) constitutes the major ISG15 specific protease which counteracts ISG15 conjugation. Remarkably, USP18 also functions as a critical negative regulator of the IFN response irrespective of its enzymatic activity. Concordantly, lack of USP18 function causes fatal interferonopathies in humans and mice. The negative regulatory function of USP18 in IFN signaling is regulated by various protein-protein interactions and its stability is controlled via proteasomal degradation. The broad repertoire of physiological functions and regulation of ISG15 and USP18 offers a variety of potential intervention strategies which might be of therapeutic use. Due to the high mutation rates of pathogens which are often species specific and constantly give rise to a variety of immune evasion mechanisms, immune effector systems are under constant evolutionarily pressure. Therefore, it is not surprising that considerable differences in ISG15 with respect to function and sequence exist even among closely related species. Hence, it is essential to thoroughly evaluate the translational potential of results obtained in model organisms especially for therapeutic strategies. This review covers existing and conceptual assay systems to target and identify modulators of ISG15, ISGylation, USP18 function, and protein-protein interactions within this context. Strategies comprise mouse models for translational perspectives, cell-based and biochemical assays as well as chemical probes.

show abstract

The in vivo ISGylome links ISG15 to metabolic pathways and autophagy upon Listeria monocytogenes infection

Cited by 75 publications

References 74 publications

Standardized Echinacea purpurea extract primes an IFN specific innate immune monocyte response via JAK1-STAT1 dependent gene expression and epigenetic control of endogenous retroviral sequences

Standardized Echinacea purpurea extract primes an IFN specific innate immune monocyte response via JAK1-STAT1 dependent gene expression and epigenetic control of endogenous retroviral sequences

Ubiquitomics: An Overview and Future

Strategies to Target ISG15 and USP18 Toward Therapeutic Applications

Contact Info

Product

Resources

About