Ask about this productRelated genes to: HERC5 Blocking Peptide
- Gene:
- HERC5 NIH gene
- Name:
- HECT and RLD domain containing E3 ubiquitin protein ligase 5
- Previous symbol:
- -
- Synonyms:
- CEB1
- Chromosome:
- 4q22.1
- Locus Type:
- gene with protein product
- Date approved:
- 2004-06-09
- Date modifiied:
- 2015-02-16
Related products to: HERC5 Blocking Peptide
Related articles to: HERC5 Blocking Peptide
- Mobilization of Long INterspersed Element-1 (LINE-1 or L1) compromises genome stability and can cause sporadic genetic diseases. Accordingly, cells have evolved multiple mechanisms to restrict L1 retrotransposition. Several interferon-stimulated genes (ISGs) that interact with cytoplasmic L1 ribonucleoproteins (RNPs), which contain the L1-encoded proteins ORF1p and ORF2p, have been identified as suppressors of L1 retrotransposition. We previously reported that the ISG protein HECT and RLD domain containing E3 ubiquitin-protein ligase 5 (HERC5) efficiently inhibits L1 retrotransposition. While HERC5 is known to restrict numerous viruses through ISGylation, how HERC5 inhibits L1 remains to be elucidated. Here, we show that HERC5 inhibits L1 retrotransposition through an ISGylation-independent mechanism. HERC5 interacts with L1 RNA and selectively reduces ORF1p levels in a manner that requires the full-length ORF1p expression. We further demonstrate that HERC5 decreases L1 translation efficiency and alters L1 RNP composition. Our comparative analysis further suggests that HERC5 may have acquired its L1-inhibitory function during the evolution of the small HERC family. These findings uncover a previously unidentified mechanism by which an ISG protein associates with and inhibits L1 and suggest a role for HERC5 as an evolutionarily adapted restriction factor that expands the repertoire of cellular defenses against retrotransposons. - Source: PubMed
Nishimori KeiLuqman-Fatah AhmadWatanabe YuzoTakahashi MariIto TakuhiroIshikawa FuyukiMiyoshi Tomoichiro - ISGylation is a ubiquitin-like enzymatic cascade that transfers the small modifier ISG15 to lysine residues of protein substrates. ISGylation occurs in a three-step enzymatic cascade involving UBA7 (E1), UBE2L6 (E2), and HERC5, TRIM25, or human homolog of ariadne (HHARI) (E3) enzymes. This mechanism regulates core cellular processes, but its role in neurodevelopmental disorders remains unclear. Here, we identified individuals with neurodevelopmental disorder phenotypes harboring biallelic gene variants and assessed their functional effects. Truncating variants result in loss of catalytic activity, protein stability, and localization. In contrast, a missense variant drives no functional defects. Fibroblasts harboring the variant p.Lys709Serfs∗45 had reduced transcript and produced a truncated and unstable UBA7 protein. These fibroblasts were unable to induce ISGylation upon interferon beta treatment, indicating a dysfunctional ISGylation system. Together, our findings identify cellular mechanisms disrupted by variants and lay the foundation for uncovering the role of the ISGylation system and UBA7 in neurodevelopment. - Source: PubMed
Publication date: 2026/03/30
Bandi VenkateshwarluVenema MyrrheWallace IonaMol Merel ONikoncuk AnitaSchot Rachelvan Slegtenhorst MarjonBijlsma Emilia KKhan AmjadWhite Susan MRius RocioDelatycki Martin BNarayanan VinodhSwatek Kirby NBarakat Tahsin StefanBustos Francisco - Post-translational modifications (PTMs) orchestrate the dynamic functional landscape of proteins, governing cellular immunity, signaling, and stress responses. Among these modifications, ISGylation, a ubiquitin-like conjugation process driven by interferon signaling, has emerged as a pivotal regulator of antiviral defense. ISG15 (Interferon-stimulated gene 15) functions through covalent attachment of its protein product to target proteins or as a secreted immunomodulator. ISG15 plays a pivotal role in antiviral immunity and cellular stress responses via ISGylation. In this review, we present an integrative structural and evolutionary analysis of ISG15 and its conjugation/deconjugation machinery, highlighting key steps of the molecular basis of ISG15 and its function. Comparative analysis of Ubiquitin and Ubiquitin-like proteins reveals the evolutionary emergence of ISG15 as a distinct modifier. Structural modeling and visualization of ISG15 elucidates its enzymatic activation via the E1 enzyme UBA7 and its conjugation through the E2 enzyme UBCH8 and E3 ligase HERC5. Cryo-EM and modeled complexes provide detailed views of domain interactions and catalytic interfaces essential for ISG15 transfer. Furthermore, we identify flexible regions in the Ubiquitin-Fold Domains (UFD) of various E1 enzymes that may underlie substrate specificity. The interaction between ISG15 and its specific protease USP18, revealing conformational changes upon substrate binding that are likely critical for de-ISGylation. Together, our findings offer a comprehensive structural framework for understanding ISGylation, paving the way for targeted therapeutic strategies in immune modulation. - Source: PubMed
Publication date: 2026/04/14
Gocenler OktayCakir NiluferTozkoparan Ceylan Cansu DenizDağ Çağdaş - The production of type I interferons (IFN-I) induced by viruses is critical for the host to resist viral infection. While emerging studies have implicated heat shock protein A2 (HSPA2) in various diseases, its specific role in antiviral immunity remains elusive. Here, using Hspa2-deficient mice and cellular models, we demonstrate that HSPA2 negatively regulates IFN-I production by targeting TANK-binding kinase 1 (TBK1). Mechanistically, HSPA2 binds to TBK1 and competes with the HECT and RLD domains containing E3 ubiquitin protein ligase 5 (HERC5) for TBK1 binding, thereby abrogating HERC5-dependent K63-linked ubiquitination of TBK1 at lysine 608 (K608), which disrupts the formation of TBK1-associated complexes and suppresses the subsequent dimerization and nuclear translocation of interferon regulatory factor 3 (IRF3), ultimately blocking IFN-I production. This study provides insights into the regulatory network governing innate immune homeostasis and identifies HSPA2 as a potential target for antiviral therapy. - Source: PubMed
Publication date: 2026/04/03
Li ChenglongLi SiruiZhang YihuaLi ManmanHong XiaowuYan Dapeng - The global burden of heart failure is escalating, marked by persistently rising prevalence, incidence, and mortality. The emerging hypothesis that the gut microbiome, as a modifiable factor, influences HF pathogenesis through immune modulation. - Source: PubMed
Publication date: 2026/01/23
Wei YingJi XuanruiMao YinanLiu YangLi Yue