Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription (PNAS, 2007, 104:13690-13695)

報告日期: 2008/10/21
報告時間: 17:10/18:00
報告學生: 鄭 烈
講評老師: 張 堯
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/971021-3.pdf

Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription

Dwayne A. Bisgrove, Tokameh Mahmoudi, Peter Henklein, and Eric Verdin

PNAS. 2007. 104(34): 13690–13695

 

Presenter: Lie Cheng

Commentator: Yao Chang Ph.D.

Presentation date: Oct 21, 2008

Room 602 of medical college

 

Abstract:

  After acute infection, HIV latency is largely developed in target resting CD4 T cells as a result of minimized viral replication and decreased viral transcriptional products. However, the mechanism leading to HIV provirus latency and transcriptional silencing were incompletely understood. Recent studies have identified several “Hot spots” in host chromosomes following HIV integration. The bromodomain-containing protein 4 (BRD4) is one of the “Hot spot” genes specifically found in populations of latent Sup T1 and Jurkat cells. Brd4 is a member of the BET (bromo and extraterminal domains) subfamily of proteins containing two bromodomains and a functionally undefined ET domain. Brd4 has been identified as an interacting partner of p-TEFb which phosphorylates polymerase II during transcription and is a crucial factor for efficient HIV transcription elongation and expression. Using coimmunoprecipitation, Western blot analysis, and a reporter assay, the authors demonstrate that a C-terminal region (153 residues) of the Brd4 was responsible for the specific interaction of the p-TEFb and residues 1337, 1346, 1351 and 1357-1359 of the Brd4 are important for the p-TEFb binding. Most importantly, this Brd4/p-TEFb interaction affected the HIV transcription and both of the p-TEFb subunits, cyclin T1 and CDK9, directly and independently interacted with BRD4 and activated the transcriptional process. In addition, the Brd4 seemed to compete with Tat for p-TEFb in HIV infected cell. Increased expression of Brd4, particularly the C-terminal peptide of Brd4, led to the inhibition of the Tat-mediated recruitment of p-TEFb to viral 5’LTR and reduced the HIV transcriptional efficiency. Similar inhibitory effect on HIV transcription could also be triggered from exogenous Brd4 C-terminal peptide. This study identifies a possibly mechanism on the control of HIV transcription, and Brd4 C-terminal peptide may be a valuable therapeutic drugs for HIV therapy.

 

Reference:

Lewinski MK, Bisgrove D, Shinn P, Chen H, Hoffmann C, Hannenhalli S, Verdin E, Berry CC, Ecker JR, Bushman FD (2005) J Virol 79:6610–6619.