Zebrafish F-box Protein fbxo3 Negatively Regulates Antiviral Response through Promoting K27-Linked Polyubiquitination of the Transcription Factors irf3 and irf7

Li, Zhi; Fan, Sijia; Wang, Jing; Chen, Xiaoyun; Liao, Qian; Liu, Xing; Ouyang, Gang; Cao, Hong; Xiao, Wuhan

doi:10.4049/jimmunol.2000305

Cited by 24 publications

(17 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…*p < 0.05. induce IFN during viral infections, IRF3 overexpression is sufficient to induce IFN without viral infection in fish because IRF3 is an IFN-inducible protein that can be activated by IFN (23). Therefore, IRF3 degradation by regulatory factors to avoid excessive activation is necessary in fish (31). In the current study, our data demonstrated that Uba1 promotes the degradation of IRF3.…”

Section: Discussionsupporting

confidence: 52%

See 1 more Smart Citation

Zebrafish Uba1 Degrades IRF3 through K48-Linked Ubiquitination to Inhibit IFN Production

Chen

Jiang

et al. 2021

The Journal of Immunology

View full text Add to dashboard Cite

Fish IFN regulatory factor 3 (IRF3) is a crucial transcription factor in the IFN activation signaling pathway, which leads to IFN production and a positive cycle. Unrestricted IFN expression results in hyperimmune responses and therefore, IFN must be tightly regulated. In the current study, we found that zebrafish Ub-activating enzyme (Uba1) negatively regulated IRF3 via the K-48 ubiquitin proteasome degradation of IRF3. First, ifn expression stimulated by spring viraemia of carp virus infection was blunted by the overexpression of Uba1 and enhanced by Uba1 knockdown. Afterward, we found that Uba1 was localized in the cytoplasm, where it interacted with and degraded IRF3. Functional domains analysis revealed that the C-terminal ubiquitin-fold domain was necessary for IRF3 degradation by Uba1 and the N-terminal DNA-binding domain of IRF3 was indispensable for the degradation by Uba1.The degradation of IRF3 was subsequently impaired by treatment with MG132, a ubiquitin proteasome inhibitor. Further mechanism analysis revealed that Uba1 induced the K48-linked Ub-proteasomal degradation of IRF3. Finally, the antiviral capacity of IRF3 was significantly attenuated by Uba1. Taken together, our study reveals that zebrafish Uba1 interacts with and activates the ubiquitinated degradation of IRF3, providing evidence of the IFN immune balance mechanism in fish.

show abstract

Section: Discussionsupporting

confidence: 52%

“…Zebrafish Forkhead box O (FOXO) 3b represses the IFN response by impeding the transcriptional activity of IRF3 (30). Another Fbox protein family member, fbxo3, promotes K27-linked polyubiquitination and the degradation of IRF3 (31). In general, the mechanisms that contribute to the termination of IRF3-IFN signaling in fish are still unclear.…”

mentioning

confidence: 99%

Zebrafish Uba1 Degrades IRF3 through K48-Linked Ubiquitination to Inhibit IFN Production

Chen

Jiang

et al. 2021

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Although the endosomal recruitments of Sec61 and p97 play vital roles in cross‐presentation, 24,29 the recycling of MHC class I molecules was also documented to increase cross‐presentation via UCH‐L1‐mediated ubiquitination 7 . At the same time, K27‐linked ubiquitination was verified to promote proteasomal degradation of irf3 and irf7 30 and inhibit UCHL3 degradation 31 . In the present study, although K27 and K48‐linked ubiquitination regulates cross‐presentation, the exact roles of the endosomal recruitments of p97/Sec61 and the recycling of MHC class I molecules in K27 or K48‐linked ubiquitination regulating cross‐presentation still need further clarification.…”

Section: Discussionmentioning

confidence: 99%

K48- and K27-mutant ubiquitin regulates adaptive immune response by affecting cross-presentation in bone marrow precursor cells

Jia

Liao

Liang

et al. 2022

Journal of Leukocyte Biology

View full text Add to dashboard Cite

K48-linked ubiquitination determines antigen degradation and plays vital roles in the process of cross-presentation of bone marrow precursor cell (BMPC)-derived dendritic cells (DCs). Although previous studies revealed that K48 and K27-linked ubiquitination regulates innate immunity, the exact roles of K48 and K27-linked ubiquitination in cross-presentation and BMPC-based adaptive immunity are still uncertain. In this study, we investigated the effects of K48-and K27-mutant ubiquitin (Ub) on BMPCbased adaptive immune response by observing the effects of MG132, Ub deficiency, and K48/K27-mutant Ub on cross-presentation, T cell proliferation, IFN-γ secretion, BMPC-based CTL priming, and thereby the efficiency of cytolytic capacity of BMPCactivate T cells. We demonstrated that MG132, Ub deficiency, and K48-mutant Ub impair cross-presentation, T cell proliferation, IFN-γ secretion, BMPC-based CTL priming, and the cytolytic capacity of BMPC-activated T cells. Moreover, although K27only Ub decreases cross-presentation, the replenishment of K27-mutant Ub restores Ub deficiency impaireds the abilities of T cell proliferation, IFN-γ secretion, CTL priming, and the cytolytic capacity of BMPC-activated T cells. Thus, these data suggest that K48-and K27-linked ubiquitination contributes to BMPC-mediated adaptive immune response by affecting BMPC cross-presentation and the cytolytic capacity by up-regulating both perforin and granzyme B in BMPC-activated T cells. K48-and K27-mutant Ub might have potential clinical therapeutic function in adaptive immune response-associated diseases.

show abstract

“…Thus, TRIM21 and PSMD14 cooperatively regulate the K27‐linked ubiquitination of IRF3 to ensure appropriate activation of type I IFN signaling. In zebrafish, E3 ligase fbxo3 induces K27‐linked ubiquitination of IRF3 and IRF7, leading to proteasomal degradation to suppress antiviral responses 79 . As the FBXO3 gene is evolutionary conserved, the biologic function of FBXO3 may show a similar effect on human beings.…”

Section: K27‐linked Ubiquitination In Innate Immunitymentioning

confidence: 99%

K27-linked noncanonic ubiquitination in immune regulation

Zhou

Zhang

2021

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Ubiquitination is a common form of posttranslational modification that has been implicated in regulating considerable immune signaling pathways. The functions of canonic K48‐ and K63‐linked ubiquitination have been well studied. However, the roles of noncanonic ubiquitination remain largely unexplored and require further investigations. There is increasing evidence suggesting that K27‐linked noncanonic ubiquitination turns out to be indispensable to both innate immune signaling and T cell signaling. In this review, we provide an overview of the latest findings related to K27‐linked ubiquitination, and highlight the crucial roles of K27‐linked ubiquitination in regulating antimicrobial response, cytokine signaling and response, as well as T cell activation and differentiation. We also propose interesting areas for better understanding how K27‐linked ubiquitination regulates immunity.

show abstract

Zebrafish F-box Protein fbxo3 Negatively Regulates Antiviral Response through Promoting K27-Linked Polyubiquitination of the Transcription Factors irf3 and irf7

Cited by 24 publications

References 62 publications

Zebrafish Uba1 Degrades IRF3 through K48-Linked Ubiquitination to Inhibit IFN Production

Zebrafish Uba1 Degrades IRF3 through K48-Linked Ubiquitination to Inhibit IFN Production

K48- and K27-mutant ubiquitin regulates adaptive immune response by affecting cross-presentation in bone marrow precursor cells

K27-linked noncanonic ubiquitination in immune regulation

Contact Info

Product

Resources

About