Abstract
The ability of anti-heat shock protein 90 (Hsp90) drugs to attenuate NF-ĸB-mediated transcription is the major basis for their anti-inflammatory properties. While the molecular mechanisms underlying this effect are not clear, they appear to be distinct in human endothelial cells. We now show for the first time that type 2 sirtuin (Sirt-2) histone deacetylase binds human NF-ĸB target gene promoter and prevents the recruitment of NF-ĸB proteins and subsequent assembly of RNA polymerase II complex in human lung microvascular endothelial cells. Hsp90 inhibitors stabilize the Sirt-2/promoter interaction and impose a “transcriptional block,” which is reversed by either inhibition or downregulation of Sirt-2 protein expression. Furthermore, this process is independent of NF-ĸB (p65) Lysine 310 deacetylation, suggesting that it is distinct from known Sirt-2-dependent mechanisms. We demonstrate that Sirt-2 is recruited to NF-ĸB target gene promoter via interaction with core histones. Upon inflammatory challenge, chromatin remodeling and core histone H3 displacement from the promoter region removes Sirt-2 and allows NF-ĸB/coactivator recruitment essential for RNA Pol II-dependent mRNA induction. This novel mechanism may have important implications in pulmonary inflammation.
Original language | English (US) |
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Pages (from-to) | L964-L974 |
Journal | American Journal of Physiology - Lung Cellular and Molecular Physiology |
Volume | 310 |
Issue number | 10 |
DOIs | |
State | Published - May 15 2016 |
Keywords
- Histone h3
- Hsp90
- Human lung endothelial cells
- NF-ĸB
- Sirt-2
ASJC Scopus subject areas
- Physiology
- Pulmonary and Respiratory Medicine
- Physiology (medical)
- Cell Biology