American Journal of Physiology - Lung Cellular and Molecular Physiology
The ability of anti-heat shock protein 90 (Hsp90) drugs to attenuate NF-κB-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-κB target gene promoter and prevents the recruitment of NF-κB 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-κB (p65) Lysine 310 deacetylation, suggesting that it is distinct from known Sirt-2-dependent mechanisms. We demonstrate that Sirt-2 is recruited to NF-κB 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-κB/coactivator recruitment essential for RNA Pol II-dependent mRNA induction. This novel mechanism may have important implications in pulmonary inflammation.
Original Publication Citation
Thangjam, G. S., Birmpas, C., Barabutis, N., Gregory, B. W., Clemens, M. A., Newton, J. R., . . . Catravas, J. D. (2016). Hsp90 inhibition suppresses NF-κB transcriptional activation via Sirt-2 in human lung microvascular endothelial cells. American Journal of Physiology - Lung Cellular and Molecular Physiology, 310(10), L964-L974. doi:10.1152/ajplung.00054.2016
Thangjam, Gagan S.; Birmpas, Charalampos; Barabutis, Nektarios; Gregory, Betsy W.; Clemens, Mary Ann; Newton, Joseph R.; Fulton, David; and Catravas, John D., "Hsp90 Inhibition Suppresses NF-κB Transcriptional Activation via Sirt-2 in Human Lung Microvascular Endothelial Cells" (2016). Bioelectrics Publications. 128.