title: A20 is induced by Kaposi sarcoma-associated herpesvirus-encoded viral FLICE inhibitory protein (vFLIP) K13 and blocks K13-induced nuclear factor-kappaB in a negative feedback manner.
abstract: Expression of A20, a negative regulator of the NF-κB pathway, is frequently lost in several subtypes of Hodgkin and non-Hodgkin lymphoma. We report that A20 is expressed in Kaposi sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma cell lines, and its expression correlates closely with the expression of KSHV-encoded viral FLICE inhibitory protein K13. Ectopic expression of K13 induced A20 expression through NF-κB-mediated activation of A20 promoter. In turn, A20 blocked K13-induced NF-κB activity and up-regulation of proinflammatory cytokines CCL20 and IL-8 in a negative feedback fashion. Both the N-terminal deubiquitinating domain and the C-terminal zinc finger domain of A20 were involved in the inhibition of K13-induced NF-κB activity. Overexpression of A20 blocked K13-induced IκBα phosphorylation, NF-κB nuclear translocation, and cellular transformation. Consistent with the above, K13-induced IκBα phosphorylation and NF-κB transcriptional activation were enhanced in A20-deficient cells. Finally, A20 was found to interact physically with K13. Taken collectively, these results demonstrate that K13 is a key determinant of A20 expression in KSHV-infected cells, and A20 is a key negative regulator of K13-induced NF-κB activity. A20 might serve to control the inflammatory response to KSHV infection and protect KSHV-infected cells from apoptosis.
authors.affiliation: Jane Ann Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA.
authors.forename: Hittu
authors.initials: H
authors.lastname: Matta
authors.forename: Ramakrishnan
authors.initials: R
authors.lastname: Gopalakrishnan
authors.forename: Vasu
authors.initials: V
authors.lastname: Punj
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: D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002460:Cell Line; D054418:Chemokine CCL20 / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C108355:CCL20 protein, human; D054418:Chemokine CCL20; D004268:DNA-Binding Proteins; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3