Pro-IL-16 recruits histone deacetylase 3 to the Skp2 core promoter through interaction with transcription factor GABP

Y Zhang, M Tuzova, ZXJ Xiao… - The Journal of …, 2008 - journals.aai.org
Y Zhang, M Tuzova, ZXJ Xiao, WW Cruikshank, DM Center
The Journal of Immunology, 2008journals.aai.org
Pro-IL-16 is a PDZ domain-containing protein expressed in T cells. Our previous work
showed that upon activation of normal T cells, pro-IL-16 mRNA and protein are diminished
in close correlation to the down-regulation of p27 KIP1 protein. In addition, we showed that
pro-IL-16 regulates the transcription of Skp2, the mechanism of which, however, remains
elusive. In this study, we identified GA binding protein β1 subunit (GABPβ1) and histone
deacetylase 3 (HDAC3) as binding partners of pro-IL-16. Interestingly, both GABPβ1 and …
Abstract
Pro-IL-16 is a PDZ domain-containing protein expressed in T cells. Our previous work showed that upon activation of normal T cells, pro-IL-16 mRNA and protein are diminished in close correlation to the down-regulation of p27 KIP1 protein. In addition, we showed that pro-IL-16 regulates the transcription of Skp2, the mechanism of which, however, remains elusive. In this study, we identified GA binding protein β1 subunit (GABPβ1) and histone deacetylase 3 (HDAC3) as binding partners of pro-IL-16. Interestingly, both GABPβ1 and HDAC3 have canonical PDZ-binding motifs and specifically bind to the first and second PDZ domain of pro-IL-16, respectively. Heat shock cognate protein 70 (HSC70) also copurified with the GST-PDZ1-containing fragment but lacks a C-terminal PDZ binding motif, suggesting that it binds through a different mechanism. We further showed that pro-IL-16 is located in a GABP transcriptional complex bound to the Skp2 promoter. In addition, we demonstrated that HDAC activity is critical for pro-IL-16-induced cell cycle arrest. Taken altogether, these data suggest that pro-IL-16 forms a complex with GABPβ1 and HDAC3 in suppressing the transcription of Skp2. Thus, this study has revealed a novel mechanism with which pro-IL-16 regulates T cell growth through the Skp2-p27 KIP1 pathway.
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