title: Phosphorylation and polyubiquitination of transforming growth factor beta-activated kinase 1 are necessary for activation of NF-kappaB by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) G protein-coupled receptor (vGPCR) protein has been shown to induce several signaling pathways leading to the modulation of host gene expression. The hijacking of these pathways facilitates the viral life cycle and leads to tumorigenesis. In the present work, we show that transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) is an important player in NF-κB activation induced by vGPCR. We observed that the expression of an inactive TAK1 kinase mutant (TAK1M) reduces vGPCR-induced NF-κB nuclear translocation and transcriptional activity. Consequently, the expression of several NF-κB target genes normally induced by vGPCR was blocked by TAK1M expression, including interleukin 8 (IL-8), Gro1, IκBα, COX-2, cIAP2, and Bcl2 genes. Similar results were obtained after downregulation of TAK1 by small interfering RNA (siRNA) technology. The expression of vGPCR recruited TAK1 to the plasma membrane, and vGPCR interacts with TAK1. vGPCR expression also induced TAK1 phosphorylation and lysine 63-linked polyubiquitination, the two markers of the kinase's activation. Finally, inhibition of TAK1 by celastrol inhibited vGPCR-induced NF-κB activation, indicating this natural compound could be used as a potential therapeutic drug against KSHV malignancies involving vGPCR.
authors.affiliation: Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA. virginie.bottero@rosalindfranklin.edu
authors.forename: Virginie
authors.initials: V
authors.lastname: Bottero
authors.forename: Nagaraj
authors.initials: N
authors.lastname: Kerur
authors.forename: Sathish
authors.initials: S
authors.lastname: Sadagopan
authors.forename: Kinjan
authors.initials: K
authors.lastname: Patel
authors.forename: Neelam
authors.initials: N
authors.lastname: Sharma-Walia
authors.forename: Bala
authors.initials: B
authors.lastname: Chandran
mesh_terms: D057809:HEK293 Cells; D006566:Herpesviridae Infections / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D054875:Ubiquitination; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D043562:Receptors, G-Protein-Coupled; D014764:Viral Proteins; D000099151:MAP Kinase Kinase Kinase 7