Inhibition of Histone Deacetylase Activity Suppresses IFN-γ Induction of Tripartite Motif 22 via CHIP-Mediated Proteasomal Degradation of IRF-1

Abstract

Tripartite motif (TRIM)22 plays an important role in IFN-mediated antiviral activity. We previously demonstrated that IFN regulatory factor (IRF)-1 was crucial for basal and IFN-induced TRIM22 transcription via binding to a novel cis-element named 5′ extended IFN-stimulating response element. In this study, we investigated the role of histone deacetylase (HDAC) activity in TRIM22 induction by IFN-γ and its underlying mechanism. We found that the HDAC activity, especially that conferred by HDAC6, was required for IFN-γ–induced TRIM22 transcription. Importantly, inhibition of HDAC activity by trichostatin A (TSA) enhanced the hyperacetylation of heat shock protein (HSP)90 and suppressed its chaperone activity for IRF-1. Further study showed that TSA treatment promoted the proteasomal degradation of IRF-1 protein via enhancing the association of IRF-1 with the ubiquitin E3 ligase carboxyl terminus of Hsc70-interacting protein. Moreover, carboxyl terminus of Hsc70-interacting protein was found to be involved in the TSA-mediated inhibitory effect on IFN-γ induction of TRIM22 as well as other IRF-1–dependent IFN-stimulated genes. This study may provide novel insight into the role of HDAC activity in the transcriptional control of IFN-stimulated gene induction.

Blunting Autoantigen-induced FOXO3a Protein Phosphorylation and Degradation Is a Novel Pathway of Glucocorticoids for the Treatment of Systemic Lupus Erythematosus

“…Western Blotting and Coimmunoprecipitation Assay-Western blotting assay and coimmunoprecipitation assay were performed as described previously (41,42 Statistical Analysis-Experimental data were presented as mean Ϯ S.E. of at least three independent experiments.…”

P42 Ebp1 regulates the proteasomal degradation of the p85 regulatory subunit of PI3K by recruiting a chaperone-E3 ligase complex HSP70/CHIP

“…A negative control was set up for each antibody by omitting the primary antibody (Supplementary Figure 6g) and specificity of primary antibodies was verified by immunoblotting throughout this research and also well confirmed by other groups as well. 37, 38, 39, 40, 41, 42, 43, 44, 45 The primary antibody incubation was completed at 4°C overnight in a humidified chamber with the following antibodies: mouse monoclonal antibody PI3K-p85 (sc-1673, Santa Cruz Biotechnology; dilution 1 : 150), 37, 38, 39, 40 mouse monoclonal antibody CHIP (sc-133066, Santa Cruz Biotechnology; dilution 1 : 200) 41, 42, 43 and mouse monoclonal antibody PCNA (Calbiochem; dilution 1 : 500). 44, 45 After incubation, each section was washed with PBS and incubated with the secondary biotinylated goat-anti mouse antibody (Vector Laboratories, Burlingame, CA, USA) for 30 min at room temperature.…”

Transcriptional Regulation of Antiviral Interferon-Stimulated Genes

“…HATs are positive regulators of transcription in general. However, HDAC activity is also essential for transcriptional induction of ISGs [59][60][61][62][63][64]. HDAC activity has been reported to be required for recruiting RNA polymerase II to the promoters of ISGs [65], although how HDACs regulate the transcriptional activation of ISG remains unclear.…”