title: HIV-1 Vpr stimulates NF-κB and AP-1 signaling by activating TAK1.
abstract: BACKGROUND
  The Vpr protein of human immunodeficiency virus type 1 (HIV-1) plays an important role in viral replication. It has been reported that Vpr stimulates the nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) signaling pathways, and thereby regulates viral and host cell gene expression. However, the molecular mechanism behind this function of Vpr is not fully understood.
  
  
  RESULTS
  Here, we have identified transforming growth factor-β-activated kinase 1 (TAK1) as the important upstream signaling molecule that Vpr associates with in order to activate NF-κB and AP-1 signaling. HIV-1 virion-associated Vpr is able to stimulate phosphorylation of TAK1. This activity of Vpr depends on its association with TAK1, since the S79A Vpr mutant lost interaction with TAK1 and was unable to activate TAK1. This association allows Vpr to promote the interaction of TAB3 with TAK1 and increase the polyubiquitination of TAK1, which renders TAK1 phosphorylation. In further support of the key role of TAK1 in this function of Vpr, knockdown of endogenous TAK1 significantly attenuated the ability of Vpr to activate NF-κB and AP-1 as well as the ability to stimulate HIV-1 LTR promoter.
  
  
  CONCLUSIONS
  HIV-1 Vpr enhances the phosphorylation and polyubiquitination of TAK1, and as a result, activates NF-κB and AP-1 signaling pathways and stimulates HIV-1 LTR promoter.
authors.forename: Ruikang
authors.initials: R
authors.lastname: Liu
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Lin
authors.forename: Rui
authors.initials: R
authors.lastname: Jia
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Geng
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.affiliation: Key Laboratory of Molecular Microbiology and Biotechnology (Ministry of Education) and Key Laboratory of Microbial Functional Genomics (Tianjin), College of Life Sciences, Nankai University, Tianjin 300071, China. juantan@nankai.edu.cn.
authors.forename: Juan
authors.initials: J
authors.lastname: Tan
authors.forename: Wentao
authors.initials: W
authors.lastname: Qiao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002460:Cell Line; D045744:Cell Line, Tumor; D016336:Gene Products, vpr / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014779:Virus Replication; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016336:Gene Products, vpr; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D000099151:MAP Kinase Kinase Kinase 7; C481053:TAB3 protein, human