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
- 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 - Pituitary adenomas (PAs) are intracranial tumours with severe clinical complications and increased morbidity. Stem cell-like characteristics play a crucial role in the initiation and progression of PAs. In this study, we identified CDK8 as a critical regulator of stemness in PA tumorigenesis. Immunohistochemical analysis demonstrated that CDK8 expression is elevated in clinical PA samples and correlates significantly with Knosp grades, indicating its potential role in parasellar invasion. Inhibition of CDK8 significantly impaired the self-renewal capacity of patient-derived PA stem-like cells (PASCs), as evidenced by reduced tumoursphere formation. To elucidate the underlying mechanism, we found that CDK8 phosphorylates the pluripotency transcription factor SOX2, thereby disrupting its interaction with the E3 ubiquitin ligase HERC5 and preventing SOX2 degradation through the ubiquitin-proteasome pathway. Moreover, pharmacological inhibition of CDK8 markedly suppressed PA cell proliferation and viability in GH3 and MMQ cell lines, primary human PA cells, and murine xenograft models. These findings revealed a novel regulatory mechanism of PA stemness and provided a promising therapeutic target for PA. - Source: PubMed
Publication date: 2026/02/26
Xie YilinWu ZeruiJi ChenxingZhang YichaoYe ZhenQiao NidanMa ZengyiChen ZhengyuanHe WenqiangSha HongyingZhao YaoYe Zhao