Abstract
This study is designed to examine the cellular functions of human Fas-associated factor 1 (FAF1) containing multiple ubiquitin-related domains. Microarray analyses revealed that interferon-stimulated genes related to the antiviral response are significantly increased in FAF1-knockdown HeLa cells. Silencing FAF1 enhanced the poly(I·C)- and respiratory syncytial virus (RSV)-induced production of type I interferons (IFNs), the target genes of interferon regulator factor 3 (IRF3). IRF3 is a key transcription factor in IFN-β signaling responsible for the host innate immune response. This study also found that FAF1 and IRF3 physically associate with IPO5/importin-β3 and that overexpression of FAF1 reduces the interaction between IRF3 and IPO5/importin-β3. These findings suggest that FAF1 negatively regulates IRF3-mediated IFN-β production and the antiviral innate immune response by regulating nuclear translocation of IRF3. We conclude that FAF1 plays a novel role in negatively regulating virus-induced IFN-β production and the antiviral response by inhibiting the translocation of active, phosphorylated IRF3 from the cytosol to the nucleus.
Highlights
This study is designed to examine the cellular functions of human Fas-associated factor 1 (FAF1) containing multiple ubiquitinrelated domains
MO); rabbit anti-interferon regulator factor 3 (IRF3), mouse anti-MAVS, mouse antitubulin, rabbit anti-histone deacetylase 1, and mouse antiactin antibodies were from Santa Cruz Biotechnology (Santa Cruz, CA); rabbit anti-Mx1 and rabbit anti-phospho-IRF3 (Ser386) were from Abcam (Cambridge, United Kingdom); rabbit anti-FAF1 and rabbit anti-glyceraldehyde-3phosphate dehydrogenase were from AbFrontier (Seoul, South Korea); rabbit antibodies specific for IRF3, phospho-IRF3 (Ser396), TBK1, TRIF, ISG15, and STAT1 were from Cell Signaling Technology (MA); mouse anti-green fluorescent protein antibody was from Life Technologies (CA); mouse anti-retinoic acid-inducible gene I (RIG-I) antibody was from Adipogen AG (CA); mouse antibodies specific for IPO5 and FAF1 were from Abnova (CA)
To examine which cellular pathway was mostly affected by silencing FAF1, we conducted Ingenuity Pathway Analysis (IPA) and found that silencing FAF1 significantly raised the expression levels of genes encoding molecules related to IFN signaling and IRF activation (Fig. 1A)
Summary
This study is designed to examine the cellular functions of human Fas-associated factor 1 (FAF1) containing multiple ubiquitinrelated domains. We conclude that FAF1 plays a novel role in negatively regulating virus-induced IFN- production and the antiviral response by inhibiting the translocation of active, phosphorylated IRF3 from the cytosol to the nucleus. Intracellular pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and nucleotide-binding oligomerization domain containing (NOD)-like receptors (NLRs), recognize pathogen-associated molecular patterns (PAMPs) and activate innate immune signaling pathways, leading to the production of type I interferons (IFN-␣/) and other cytokines. Single-stranded or double-stranded viral RNAs accumulated inside cells after infection are recognized by RLRs and TLR3, which recruit the adaptor proteins mitochondrial antiviral signaling protein (MAVS) and TRIF, respectively [8, 9] These adaptor proteins, MAVS and TRIF, recruit the kinases TBK1 and IB kinase ε (IKKε), which activate IRF3 by phosphorylating the C-terminal region of IRF3 at seven Ser/Thr residues RAUL, a major ubiquitin E3 ligase, ubiquitinates IRF3 regardless of its phosphorylation status [15], while the E3 ubiquitin
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