title: HMBA Enhances Prostratin-Induced Activation of Latent HIV-1 via Suppressing the Expression of Negative Feedback Regulator A20/TNFAIP3 in NF-κB Signaling.
abstract: In the past decade, much emphasis has been put on the transcriptional activation of HIV-1, which is proposed as a promised strategy for eradicating latent HIV-1 provirus. Two drugs, prostratin and hexamethylene bisacetamide (HMBA), have shown potent effects as inducers for releasing HIV-1 latency when used alone or in combination, although their cellular target(s) are currently not well understood, especially under drug combination. Here, we have shown that HMBA and prostratin synergistically release HIV-1 latency via different mechanisms. While prostratin strongly stimulates HMBA-induced HIV-1 transcription via improved P-TEFb activation, HMBA is capable of boosting NF-κB-dependent transcription initiation by suppressing prostratin-induced expression of the deubiquitinase A20, a negative feedback regulator in the NF-κB signaling pathway. In addition, HMBA was able to increase prostratin-induced phosphorylation and degradation of NF-κB inhibitor IκBα, thereby enhancing and prolonging prostratin-induced nuclear translocation of NF-κB, a prerequisite for stimulation of transcription initiation. Thus, by blocking the negative feedback circuit, HMBA functions as a signaling enhancer of the NF-κB signaling pathway.
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Duchu
authors.initials: D
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China; Department of Genetics, Xuzhou Medical College, Xuzhou, Jiangsu 221000, 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: Jude Juventus
authors.initials: JJ
authors.lastname: Aweya
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: Meihua
authors.initials: M
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
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: Min
authors.identifier: 0000-0001-5183-1187
authors.initials: M
authors.lastname: Liu
mesh_terms: D000081:Acetamides / Q000008:administration & dosage*; D004357:Drug Synergism; D025461:Feedback, Physiological / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics; D010703:Phorbol Esters / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D042925:Positive Transcriptional Elongation Factor B / Q000096:biosynthesis; D011533:Proviruses / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000081:Acetamides; D020672:I-kappa B Proteins; D016328:NF-kappa B; D010703:Phorbol Esters; C070999:prostratin; D042925:Positive Transcriptional Elongation Factor B; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C014026:hexamethylene bisacetamide