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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.
AuthorsXiaohong Du, Fang Meng, Di Peng, Zining Wang, Wei Ouyang, Yu Han, Yayun Gu, Lingbo Fan, Fei Wu, Xiaodong Jiang, Feng Xu, F Xiao-Feng Qin
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 203 Issue 4 Pg. 1012-1020 (08 15 2019) ISSN: 1550-6606 [Electronic] United States
PMID31308089 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2019 by The American Association of Immunologists, Inc.
Chemical References
  • Interferon Type I
  • FBXO6 protein, human
  • SKP Cullin F-Box Protein Ligases
Topics
  • Cell Line
  • Humans
  • Interferon Type I (immunology)
  • SKP Cullin F-Box Protein Ligases (immunology)
  • Virus Diseases (immunology)

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