Year: 2026
Type: article
Abstract: In innate immunity, effective activation of the NF-κB signaling pathway is crucial for initiating inflammatory responses and eliminating invading bacteria, and its precise regulation relies heavily on the ubiquitin-proteasome system. Ubiquitination, a pivotal post-translational modification, is specifically catalyzed by E3 ubiquitin ligases that determine substrate selection. Ubiquitination of the adaptor protein MyD88 is critical for immune signaling; however, its regulatory mechanism in teleost fish, especially regarding the involvement of E3 ubiquitin ligases remains unclear. Among these E3 ubiquitin ligases, SMAD ubiquitylation regulatory factor 1 (Smurf1), while important in multiple signaling pathways, has not been reported to regulate antibacterial immunity in teleost fish. Thus, we systematically investigated Smurf1’s role and molecular mechanism in this immune process, using Miichthys miiuy as a model. Reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) analysis in M. miiuy kidney cells (MKC) revealed that Smurf1 overexpression suppressed pro-inflammatory cytokine expression and enhanced Vibrio anguillarum proliferation and adhesion, while Smurf1 knockdown exerted the opposite effects. Mechanistically, Smurf1 directly interacts with MyD88, promoting MyD88 proteasomal degradation through K48-linked polyubiquitination, which is dependent on Smurf1’s E3 ligase activity (C704A) and HECT domain, as the C704A mutation or HECT domain deletion abolished this function. Luciferase reporter assays confirmed that Smurf1-mediated MyD88 degradation inhibits NF-κB signaling, thereby negatively regulating innate immunity and maintaining inflammatory homeostasis. Our findings reveal a mechanism by which Smurf1 balances immunity and homeostasis via MyD88 ubiquitination, providing valuable insights into vertebrate immune regulation.
Source: 动物学研究
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: diamond
Award: G76742753
OpenAlex ID: W7125592485