Pro-IL-16 recruits histone deacetylase 3 to the Skp2 core promoter through interaction with transcription factor GABP.
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 p27KIP1 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 beta1 subunit (GABPbeta1) and histone deacetylase 3 (HDAC3) as binding partners of pro-IL-16. Interestingly, both GABPbeta1 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 GABPbeta1 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-p27KIP1 pathway.
Zhang
Yujun
Y
Pulmonary Center, Department of Biochemistry, Boston University School of Medicine, MA 02118, USA. yujunz@bu.edu
Tuzova
Marina
M
Xiao
Zhi-Xiong J
ZX
Cruikshank
William W
WW
Center
David M
DM
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051268:GA-Binding Protein Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019410:Interleukin-16 / Q000378:metabolism*; D019169:Jurkat Cells; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D000099186:Histone Deacetylase 3
D004791:Enzyme Inhibitors; D051268:GA-Binding Protein Transcription Factor; D050883:HSC70 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D019410:Interleukin-16; D011498:Protein Precursors; D044786:S-Phase Kinase-Associated Proteins; D000099186:Histone Deacetylase 3; C495662:GABPB1 protein, human; C105950:interleukin 16 precursor; C012589:trichostatin A