The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a β-catenin-dependent pathway

Yang, P., et al. Nature Immunology. 11, 487-495 (2010)

Speaker: Fu-I Tsai (蔡馥儀)                                 Time: 15:10~16:00, Jan. 5, 2010

Commentator: Dr. Pin Lin (凌斌 老師)              Place: Room 601

Abstract:

Nucleic acids in cytoplasm were found to be recognized by innate sensors and promote the production of type I interferon during microbial infection. By using siRNA library screening, the authors investigate that transfection of LRRFIP1 (Leucine-rich repeat flightless-interacting protein 1)-specific siRNA in mouse primary peritoneal macrophages can reduce IFN-β production induced by intracellular pathogen Lesteria monocytogenes infection. Further experiment demonstrated that LRRFIP1 can recognized poly(dG:dC), poly(dA:dT) and poly(I:C) resulting in IFN-β production. Studies on LRRFIP1 have shown that LRRFIP1 can interact with β-catenin and coactivator p300 to mediate β-catenin-dependent transcription¹ . Knock-down of β-catenin in vitro and in vivo also reduced the level of IFN-β induced by L. monocytogenes and vesicular stomatitis virus (VSV), which indicate that IFN-β production triggered by microbial infection is β-catenin-dependent. Subsequent experiments investigated that β-catenin can bind IRF3 transactivation domain through its C-terminal domain by generating truncation mutants. Besides, previous studies have shown that IRF3 can interact with p300/CBP and promote hyperacetylation of H3 and H4 to activate IFN-β gene expression². To demonstrate whether β-catenin has a role between LRRFIP1 and IRF3 induced IFN-β gene activation by p300 and hyperacetylation of H3 and H4, chromatin-immunoprecipitation (ChIP) assay was used to showed that β–catenin can recruit to Ifnb1 promoter after poly(I:C) stimulation. Furthermore, poly(I:C) stimulation triggered p300 recruitment and acetylation of H3 and H4 in Ifnb1 promoter region were lower in β-catenin-deficient macrophages. All of these results indicate that β-catenin can bind to IRF3 and enhance IFN-β expression through recruitment of p300 and hyperacetylation of H3 and H4 in Ifnb1 promoter region. Collectively, this research demonstrated that LRRFIP1 is a cytosolic nucleic sensor, and LRRFIP1 can promote type I interferon production through β-catenin as well as IRF3-dependent pathway.

References:

1. Lee, Y. H., et al. Interplay of Fli-I and FLAP1 for regulation of β-catenin-dependent transcription. Nucleic Acids Res. 34, 5052–5059 (2006).

2. Parekh, B.S., et al. Virus infection leads to localized hyperacetylation of histones H3 and H4 at the IFN-β promoter. Mol. Cell. 3, 125–129 (1999).