title: Kaposi's sarcoma associated herpesvirus encoded viral FLICE inhibitory protein K13 activates NF-κB pathway independent of TRAF6, TAK1 and LUBAC.
abstract: BACKGROUND
  Kaposi's sarcoma associated herpesvirus encoded viral FLICE inhibitory protein (vFLIP) K13 activates the NF-κB pathway by binding to the NEMO/IKKγ subunit of the IκB kinase (IKK) complex. However, it has remained enigmatic how K13-NEMO interaction results in the activation of the IKK complex. Recent studies have implicated TRAF6, TAK1 and linear ubiquitin chains assembled by a linear ubiquitin chain assembly complex (LUBAC) consisting of HOIL-1, HOIP and SHARPIN in IKK activation by proinflammatory cytokines.
  
  
  RESULTS
  Here we demonstrate that K13-induced NF-κB DNA binding and transcriptional activities are not impaired in cells derived from mice with targeted disruption of TRAF6, TAK1 and HOIL-1 genes and in cells derived from mice with chronic proliferative dermatitis (cpdm), which have mutation in the Sharpin gene (Sharpin(cpdm/cpdm)). Furthermore, reconstitution of NEMO-deficient murine embryonic fibroblast cells with NEMO mutants that are incapable of binding to linear ubiquitin chains supported K13-induced NF-κB activity. K13-induced NF-κB activity was not blocked by CYLD, a deubiquitylating enzyme that can cleave linear and Lys63-linked ubiquitin chains. On the other hand, NEMO was required for interaction of K13 with IKK1/IKKα and IKK2/IKKβ, which resulted in their activation by "T Loop" phosphorylation.
  
  
  CONCLUSIONS
  Our results demonstrate that K13 activates the NF-κB pathway by binding to NEMO which results in the recruitment of IKK1/IKKα and IKK2/IKKβ and their subsequent activation by phosphorylation. Thus, K13 activates NF-κB via a mechanism distinct from that utilized by inflammatory cytokines. These results have important implications for the development of therapeutic agents targeting K13-induced NF-κB for the treatment of KSHV-associated malignancies.
authors.affiliation: Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America.
authors.forename: Hittu
authors.initials: H
authors.lastname: Matta
authors.forename: Ramakrishnan
authors.initials: R
authors.lastname: Gopalakrishnan
authors.forename: Ciaren
authors.initials: C
authors.lastname: Graham
authors.forename: Bhairavi
authors.initials: B
authors.lastname: Tolani
authors.forename: Akshat
authors.initials: A
authors.lastname: Khanna
authors.forename: Han
authors.initials: H
authors.lastname: Yi
authors.forename: Yulan
authors.initials: Y
authors.lastname: Suo
authors.forename: Preet M
authors.initials: PM
authors.lastname: Chaudhary
mesh_terms: D000818:Animals; D002908:Chronic Disease; D003872:Dermatitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D046912:Multiprotein Complexes; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D014764:Viral Proteins; D000099151:MAP Kinase Kinase Kinase 7; C491731:IKBKG protein, human; C514981:NEMO protein, mouse; C481275:viral FLIP protein, Human herpesvirus 8