A Novel Function of F-Box Protein FBXO17 in Negative Regulation of Type I IFN Signaling by Recruiting PP2A for IFN Regulatory Factor 3 Deactivation

Abstract

The F-box proteins were originally identified as the key component of SKP1-Cullin1-F-box E3 ligase complexes that control the stability of their specific downstream substrates essential for cell growth and survival. However, the involvement of these proteins in type I IFN (IFN-I) signaling during innate immunity has not been investigated. In this study we report that the F-box protein FBXO17 negatively regulates IFN-I signaling triggered by double-strand DNA, RNA, or viral infection. We found that FBXO17 specifically interacts with IFN regulatory factor 3 (IRF3) and decreases its dimerization and nuclear translocation. The decrease of IRF3 dimerization and nuclear translocation is due to the recruitment of protein phosphatase 2 (PP2A) mediated by FBXO17, resulting in IRF3 dephosphorylation. Interestingly, PP2A recruitment does not require the F-box domain but instead the F-box associated region of the protein; thus, the recruitment is independent of the canonical function of the SKP1-Cullin1-F-box family of E3 ligase. Together, our studies identify a previously unreported role of FBXO17 in regulating IFN-I signaling and further demonstrate a novel mechanism for IRF3 deactivation by F-box protein-mediated recruitment of PP2A.

cGAS/STING axis mediates a topoisomerase II inhibitor–induced tumor immunogenicity

“…Western blot, immunofluorescence, and immunohistochemistry. The procedures for protein sample preparation from cell cultures, protein quantification, Western blot, and data analyses were performed as previously described (57). The following antibodies were used for Western blot analyses: Gaussia (NEB, catalog E8023), actin (Milli-poreSigma, catalog A3854), cGAS (CST, catalog 31659), STING (CST, catalog 13647), STAT1 (CST, catalog 14994), p-STAT1 (CST, catalog 9167), p-p65 (CST, catalog 3036), p65 (CST, catalog 8248), TBK1 (CST, catalog 3504), p-IRF3 (CST, catalog 29047), and IRF3 (CST, catalog 4302).…”

ToxoplasmaF-Box Protein 1 is Required for Daughter Cell Scaffold Function During Parasite Replication

“…We are currently unable to differentiate whether TgFBXO1 acts in a SCF-E3 ubiquitin ligase dependent or independent manner [15, 54, 55]. It is possible that TgFBXO1 functions in IMC protein ubiquitylation to regulate their turnover and/or targeting during endodyogeny.…”

“…It is also possible that TgFBXO1 is itself an SCF-E3 substrate and its ubiquitylation is required during endodyogeny for either trafficking of TgFBXO1 from the IMC to the DCS or for its turnover from the mature IMC early during endodyogeny. It is noteworthy that a parasite deubiquitinase, TgOTUD3 [15, 54, 55, 57, 58] was recently reported to coordinate mitosis and cytokinesis by properly matching the correct numbers of centrosomes with numbers of daughter buds. However, we do not believe that TgFBXO1 functions in this manner because in contrast to TgOTUD3, loss of TgFBXO1 leads to unmatched numbers of outer centrosome cores and daughter buds without an increase in parasite ploidy.…”

SCFFBXO17 E3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3β in lung epithelia

“…GSK3␤ also pro-motes neuroinflammation in glial cells from mice treated with LPS through STAT3 activation (47). A recent study by Peng and colleagues (48) demonstrated that FBXO17 reduces type I IFN signaling through recruitment of protein phosphatase 2A (PP2A) for dephosphorylation of interferon recruitment factor 3 (IRF3) in A549 and HEK293T cells. Intriguingly, these effects were not related to SCF E3 ligase function and were independent of the F-box domain and ubiquitin-proteasome pathway.…”