Protein modification with ISG15 blocks coxsackievirus pathology by antiviral and metabolic reprogramming

Kespohl, Meike; Bredow, Clara; Klingel, Karin; Voß, Martin; Paeschke, Anna; Zickler, Martin; Poller, Wolfgang; Kaya, Ziya; Eckstein, Johannes; Fechner, Henry; Spranger, Joachim; Fähling, Michael; Wirth, Eva K.; Radoshevich, Lilliana; Thery, Fabien; Impens, Francis; Berndt, Nikolaus; Knobeloch, Klaus–Peter; Beling, Antje

doi:10.1126/sciadv.aay1109

Cited by 30 publications

(47 citation statements)

References 60 publications

(124 reference statements)

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“…4H-I). As a third ISG15- sensitive viral pathogen we tested CVB3, a Picornavirus that can lead to cardiomyopathy and that is known to be ISG15-sensitive 11,12 (Supplementary Fig. 7B).…”

Section: Resultsmentioning

confidence: 99%

“…The absence of RNF213 protein expression was confirmed by immunoblotting. The ISG15 knockout HeLa cell line was generated as previously described (Kespohl et al, 2020).…”

Section: Generation Of Knockout Cell Linesmentioning

confidence: 99%

“…ISG15 has potent antiviral effects both in vitro and in vivo 8 . In fact, mice which lack ISG15 are unable to control various viral pathogens including clinically relevant etiologic agents such as Influenza 9 , human respiratory syncytial virus 10 and coxsackievirus 11,12 . ISG15's crucial antiviral role is bolstered by the variety of viral evasion strategies targeting the ISGylation pathway, either by interfering with ISG15 conjugation 1, 13 or by expressing ISG15specific proteases that lead to reversible [14][15][16][17] or irreversible deconjugation 18 .…”

Section: Introductionmentioning

confidence: 99%

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Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity

Thery

Martina

Asselman

et al. 2021

Preprint

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ISG15 is an interferon-stimulated, ubiquitin-like protein that can conjugate to substrate proteins (ISGylation) to counteract microbial infection, but the underlying mechanisms remain elusive. Here, we used a viral-like particle trapping technology to identify ISG15-binding proteins and discovered Ring Finger Protein 213 (RNF213) as an ISG15 interactor and cellular sensor of ISGylated proteins. RNF213 is a poorly-characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. We found that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We showed that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting infection with Listeria monocytogenes, herpes simplex virus 1 (HSV-1), human respiratory syncytial virus (RSV) and coxsackievirus B3 (CVB3), and we observed a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide novel molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector.

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“…4H-I). As a third ISG15- sensitive viral pathogen we tested CVB3, a Picornavirus that can lead to cardiomyopathy and that is known to be ISG15-sensitive 11,12 (Supplementary Fig. 7B).…”

Section: Resultsmentioning

confidence: 99%

“…The absence of RNF213 protein expression was confirmed by immunoblotting. The ISG15 knockout HeLa cell line was generated as previously described (Kespohl et al, 2020).…”

Section: Generation Of Knockout Cell Linesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity

Thery

Martina

Asselman

et al. 2021

Preprint

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“…In A/J mice, where the severe CV-triggered pathology is primarily attributed to a sepsis-like cytokine storm and distributive shock condition, ip activity is on the whole detrimental [ 2 ]. Unlike C57BL/6 mice [ 28 ], A/J mice can also be used as a model organism to investigate troponin I-directed cardiac autoimmunity [ 20 ]. AM is known to be triggered by viral infection [ 46 ] or by therapy with immune checkpoint inhibitors (ICI) targeting, e.g., the PD-1/PD-1L pathway [ 25 ], with ICI-related myocarditis being a severe, if rare, side effect in cancer immunotherapy [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Mitigated viral myocarditis in A/J mice by the immunoproteasome inhibitor ONX 0914 depends on inhibition of systemic inflammatory responses in CoxsackievirusB3 infection

et al. 2021

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A preclinical model of troponin I-induced myocarditis (AM) revealed a prominent role of the immunoproteasome (ip), the main immune cell-resident proteasome isoform, in heart-directed autoimmunity. Viral infection of the heart is a known trigger of cardiac autoimmunity, with the ip enhancing systemic inflammatory responses after infection with a cardiotropic coxsackievirusB3 (CV). Here, we used ip-deficient A/J-LMP7−/− mice to investigate the role of ip-mediated effects on adaptive immunity in CV-triggered myocarditis and found no alteration of the inflammatory heart tissue damage or cardiac function in comparison to wild-type controls. Aiming to define the impact of the systemic inflammatory storm under the control of ip proteolysis during CV infection, we targeted the ip in A/J mice with the inhibitor ONX 0914 after the first cycle of infection, when systemic inflammation has set in, well before cardiac inflammation. During established acute myocarditis, the ONX 0914 treatment group had the same reduction in cardiac output as the controls, with inflammatory responses in heart tissue being unaffected by the compound. Based on these findings and with regard to the known anti-inflammatory role of ONX 0914 in CV infection, we conclude that the efficacy of ip inhibitors for CV-triggered myocarditis in A/J mice relies on their immunomodulatory effects on the systemic inflammatory reaction.

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“…ISGylation induced anti-viral in non-hematopoietic cells during Coxsackievirus B3 (CVB3) infection. The authors suggest that ISG conjugation to anti-viral effectors IFIT1 and IFIT3 blocks ubiquitination-dependent degradation and stabilizes these proteins leading to an enhanced anti-viral response ( Figure 2 ) [ 60 ]. CVB3 encodes a protease (2APro) that mediates host cell translational shut off by cleavage of eukaryotic translation factor 4γ1 (eIF4G1), which binds to RNA cap involved in cap-dependent translation.…”

Section: Protein-based Ptmsmentioning

confidence: 99%

Role of Host-Mediated Post-Translational Modifications (PTMs) in RNA Virus Pathogenesis

Kumar

Mehta

Mishra

et al. 2020

IJMS

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Being opportunistic intracellular pathogens, viruses are dependent on the host for their replication. They hijack host cellular machinery for their replication and survival by targeting crucial cellular physiological pathways, including transcription, translation, immune pathways, and apoptosis. Immediately after translation, the host and viral proteins undergo a process called post-translational modification (PTM). PTMs of proteins involves the attachment of small proteins, carbohydrates/lipids, or chemical groups to the proteins and are crucial for the proteins’ functioning. During viral infection, host proteins utilize PTMs to control the virus replication, using strategies like activating immune response pathways, inhibiting viral protein synthesis, and ultimately eliminating the virus from the host. PTM of viral proteins increases solubility, enhances antigenicity and virulence properties. However, RNA viruses are devoid of enzymes capable of introducing PTMs to their proteins. Hence, they utilize the host PTM machinery to promote their survival. Proteins from viruses belonging to the family: Togaviridae, Flaviviridae, Retroviridae, and Coronaviridae such as chikungunya, dengue, zika, HIV, and coronavirus are a few that are well-known to be modified. This review discusses various host and virus-mediated PTMs that play a role in the outcome during the infection.

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Protein modification with ISG15 blocks coxsackievirus pathology by antiviral and metabolic reprogramming

Cited by 30 publications

References 60 publications

Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity

Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity

Mitigated viral myocarditis in A/J mice by the immunoproteasome inhibitor ONX 0914 depends on inhibition of systemic inflammatory responses in CoxsackievirusB3 infection

Role of Host-Mediated Post-Translational Modifications (PTMs) in RNA Virus Pathogenesis

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