4.7 Article

Quantitative Proteomics of the CDK9 Interactome Reveals a Function of the HSP90-CDC37-P-TEFb Complex for BETi-Induced HIV-1 Latency Reactivation

Journal

JOURNAL OF PROTEOME RESEARCH
Volume 22, Issue 9, Pages 2880-2889

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jproteome.3c00162

Keywords

HSP90; P-TEFb; HIV latency reactivation; Brd4; quantitative proteomics

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Brd4 has attracted significant attention as a potential drug target due to its involvement in oncogenesis, inflammation, and HIV-1 transcription. Mass spectrometry-based quantitative proteomics identified 352 proteins that interact with CDK9, among which the increased bindings of HSP90 and CDC37 were particularly notable. The findings advance our understanding of how the HSP90-CDC37-P-TEFb complex regulates HIV-1 latency.
Brd4 has been intensively investigated as a promisingdrug targetbecause of its implicated functions in oncogenesis, inflammation,and HIV-1 transcription. The formation of the Brd4-P-TEFb (CDK9/CyclinT1) complex and its regulation of transcriptional elongation are criticalfor HIV latency reactivation and expression of many oncogenes. Tofurther investigate the mechanism of the Brd4-P-TEFb complex in controllingelongation, mass spectrometry-based quantitative proteomics of theCDK9 interactome was performed. Upon treatment with the selectiveBET bromodomain inhibitor JQ1, 352 proteins were successfully identifiedwith high confidence as CDK9-interacting proteins. Among them, increasedbindings of HSP90 and CDC37 to CDK9 were particularly striking, andour data suggest that the HSP90-CDC37-P-TEFb complex is involved incontrolling the dynamic equilibrium of the P-TEFb complex during BETi-inducedreactivation of HIV-1 latency. Furthermore, the HSP90-CDC37-P-TEFbcomplex directly regulates HIV-1 transcription and relies on recruitmentby heat shock factor 1 (HSF1) for binding to the HIV-1 promoter. Theseresults advance the understanding of HSP90-CDC37-P-TEFb in HIV-1 latencyreversal and enlighten the development of potential strategies toeradicate HIV-1 using a combination of targeted drugs.

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