ArticleJournal of virology2024
ISGylation of the SARS-CoV-2 N protein by HERC5 impedes N oligomerization and thereby viral RNA synthesis.
Article in Journal of virology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed.
- Article
- Beyond the Capsid: How Can Post-Translational Modifications Modulate the Multifunctionality of the Orthoflavivirus Capsid Protein?Molecules (Basel, Switzerland) · 2026Review
- Modification of PCNA by ISG15 plays a crucial role in porcine deltacoronavirus infection.Veterinary research · 2026Article
- SARS-CoV-2 nonstructural protein 3 remodels the phosphorylation of target proteins via protein-protein interactions.Microbiology spectrum · 2026Article
- Convergent hub pathways targeted by IAV, SARS-CoV-2, and RSV in type II alveolar epithelial cells: molecular mechanisms and therapeutic implications.Frontiers in immunology · 2026Review
- Rewriting the viral script: post-translational modifications orchestrating SARS-CoV-2 pathogenesis and immune evasion.Frontiers in microbiology · 2026Review
- The roles of post-translational modifications in the pathogenesis of RNA viruses: allies or adversaries?Frontiers in microbiology · 2026Review
- SARS-CoV-2-host and interactions: the dual roles of E3 ubiquitin ligases and ubiquitin-like modification mechanisms in viral infection.Frontiers in immunology · 2026Review
- Ubiquitination and ubiquitin-like modifications in metabolic dysfunction-associated steatotic liver disease: mechanisms and implications.BMB reports · 2025Review
- Review
- MDA5 ISGylation is crucial for immune signaling to control viral replication and pathogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- PLSCR1 suppresses SARS-CoV-2 infection by downregulating cell surface ACE2.Journal of virology · 2025Article
- ISGylation: is our genome yearning for such a modification?Acta biochimica et biophysica Sinica · 2025Review
- Article
- Coronavirus nucleocapsid proteins: a multifaceted modulator in the innate immune evasion.Frontiers in microbiology · 2025Review
- Suppression of SARS-CoV-2 nucleocapsid protein dimerization by ISGylation and its counteraction by viral PLpro.Frontiers in microbiology · 2024Article
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Abstract
Interferon (IFN)-stimulated gene 15 (ISG15), a ubiquitin-like protein, is covalently conjugated to host immune proteins such as MDA5 and IRF3 in a process called ISGylation, thereby promoting type I IFN induction to limit the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, whether SARS-CoV-2 proteins can be directly targeted for ISGylation remains elusive. In this study, we identified the nucleocapsid (N) protein of SARS-CoV-2 as a major substrate of ISGylation catalyzed by the host E3 ligase HERC5; however, N ISGylation is readily removed through deISGylation by the papain-like protease (PLpro) activity of NSP3. Mass spectrometry analysis identified that the N protein undergoes ISGylation at four lysine residues (K266, K355, K387, and K388), and mutational analysis of these sites in the context of a SARS-CoV-2 replicon (N-4KR) abolished N ISGylation and alleviated ISGylation-mediated inhibition of viral RNA synthesis. Furthermore, our results indicated that HERC5 targets preferentially phosphorylated N protein for ISGylation to regulate its oligomeric assembly. These findings reveal a novel mechanism by which the host ISGylation machinery directly targets SARS-CoV-2 proteins to restrict viral replication and illuminate how an intricate interplay of host (HERC5) and viral (PLpro) enzymes coordinates viral protein ISGylation and thereby regulates virus replication.IMPORTANCEThe role of protein ISGylation in regulating host cellular processes has been studied extensively; however, how ISG15 conjugation influences the activity of viral proteins, particularly coronaviral proteins, is largely unknown. Our study uncovered that the nucleocapsid (N) protein of SARS-CoV-2 is ISGylated by the HERC5 ISGylation machinery and that this modification impedes the functional assembly of N into oligomers ultimately inhibiting viral RNA synthesis. This antiviral restriction mechanism is antagonized by the PLpro deISGylation activity of SARS-CoV-2 NSP3. This study deepens our understanding of SARS-CoV-2 protein regulation by posttranslational modifications and may open new avenues for designing antiviral strategies for COVID-19.
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