Noncanonical Role of FBXO6 in Regulating Antiviral Immunity

Abstract

The evolutionarily conserved F-box family of proteins are well known for their role as the key component of SKP1-Cullin1-F-box (SCF) E3 ligase in controlling cell cycle, cell proliferation and cell death, carcinogenesis, and cancer metastasis. However, thus far, there is only limited investigation on their involvement in antiviral immunity. In contrast to the canonical function of FBXO6 associated with SCF E3 ligase complex, we report, in this study, that FBXO6 can also potently regulate the activation of IFN-I signaling during host response to viral infection by targeting the key transcription factor IFN-regulatory factor 3 (IRF3) for accelerated degradation independent of SCF in human embryonic kidney cells (HEK293T) and human lung cancer epithelial cells (A549). Structure and function delineation has further revealed that FBXO6 interacts with IAD domain of IRF3 through its FBA region to induce ubiquitination and degradation of IRF3 without the involvement of SCF. Thus, our studies have identified a general but, to our knowledge, previously unrecognized role and a novel noncanonical mechanism of FBXO6 in modulating IFN-I-mediated antiviral immune responses, which may protect the host from immunopathology of overreactive and harmful IFN-I production.

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

“…F-box proteins were originally identified as a component of the SKP1-Cullin1-F-box (SCF) E3 ligase complex that initiate the ubiquitin-mediated destruction of their specific downstream substrates (25). Extensive studies have indicated that F-box proteins play pivotal roles in multiple cellular processes, such as cell growth and survival, cellular immune response, carcinogenesis, and cancer metastasis (26)(27)(28)(29)(30)(31)(32), through ubiquitylation, and subsequent degradation of target proteins (25,33). Some F-box proteins have been reported to regulate the type I IFN signaling (IFN-I).…”

Identification of key genes and pathways in the hPSC-derived lungs infected by the SARS-CoV-2

“…FBXO44 Mediates BRCA1 Ubiquitination and protein metabolism 50 . The activation of IFN-I signaling can be reversed by the FBXO6 51 . Our analysis further discovered that antigen processing (Ubiquitination & Proteasome degradation) and mRNA Splicing are involved in the SARS-CoV-2 infection by analyzing the Reactome Pathway Database.…”

Fbxo6 is a differentially expressed gene in the blood of patients with Crohn’s Disease.

“…There are limited studies describing a role for FBXO6 in the immune system (14,15). In one study, investigators found that in the context of experimental viral infection, FBXO6 targeted the interferon regulatory factor 3 (IRF3) for degradation (14).…”

“…There are limited studies describing a role for FBXO6 in the immune system (14,15). In one study, investigators found that in the context of experimental viral infection, FBXO6 targeted the interferon regulatory factor 3 (IRF3) for degradation (14). The authors proposed that FBXO6 degradation of IRF3 functioned to limit the antiviral response by down-regulating interferon signaling and prevent damage by an overactive antiviral response.…”

“…In one patient dataset (1), the quantity of FBXO6 mRNA was present at significantly higher levels in the blood of patients with CD as compared to non-affected controls. FBXO6 has multiple protein partners (11) and multiple cellular functions: in endoplasmic reticulum (ER) stress signaling associated with the unfolded protein responses (12), in the cell cycle (13) and in immunity (14,15). FBXO6 may be a molecule of interest in studying the multiple factors that contribute to the establishment of the inflammatory phenotype in Crohn's Disease.…”