title: Protein kinase D3 is essential for prostratin-activated transcription of integrated HIV-1 provirus promoter via NF-κB signaling pathway.
abstract: Prostratin has been proposed as a promising reagent for eradicating the latent HIV-1 provirus by inducing HIV-1 transcription activation. The molecular mechanism of this activation, however, is far from clear. Here, we show that the protein kinase D3 (PKD3) is essential for prostratin-induced transcription activation of latent HIV-1 provirus. First, silencing PKD3, but not the other members of PKD family, blocked prostratin-induced transcription of HIV-1. Second, overexpressing the constitutively active form of PKD3, but not the wild-type or kinase-dead form of PKD3, augmented the expression of HIV-1. Consistent with this observation, we found that prostratin could trigger PKD3 activation by inducing the phosphorylation of its activation loop. In addition, we identified PKCε of the novel PKC subfamily as the upstream kinase for this phosphorylation. Finally, the activation effect of PKD3 on HIV-1 transcription was shown to depend on the presence of κB element and the prostratin-induced activation of NF-κB, as indicated by the fact that silencing PKD3 blocked prostratin-induced NF-κB activation and NF-κB-dependent HIV-1 transcription. Therefore, for the first time, PKD3 is implicated in the transcription activation of latent HIV-1 provirus, and our results revealed a molecular mechanism of prostratin-induced HIV-1 transcription via PKCε/PKD3/NF-κB signaling pathway.
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China ; Department of Neurobiology, Xuzhou Medical College, Xuzhou, Jiangsu 221009, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Xinxing
authors.initials: X
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Jiangfang
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Sijia
authors.initials: S
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Yanheng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Ruichuan
authors.identifier: 0000-0002-7891-9231
authors.initials: R
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Runzhong
authors.identifier: 0000-0003-4966-4054
authors.initials: R
authors.lastname: Liu
mesh_terms: D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism; D011533:Proviruses / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D016662:Virus Integration / Q000187:drug effects / Q000235:genetics*
chemical_list: D007211:Indoles; D008301:Maleimides; D016328:NF-kappa B; D010703:Phorbol Esters; C070999:prostratin; C119190:protein kinase C nu; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; C088060:bisindolylmaleimide