A20 Is Induced by Kaposi Sarcoma-associated Herpesvirus-encoded Viral FLICE Inhibitory Protein (vFLIP) K13 and Blocks K13-induced Nuclear Factor-kappa B in a Negative Feedback Manner

作者：Matta Hittu; Gopalakrishnan Ramakrishnan; Punj Vasu; Yi Han; Suo Yulan; Chaudhary Preet M^*

来源：Journal of Biological Chemistry, 2011, 286(24): 21555-21564.

DOI：10.1074/jbc.M111.224048

Expression of A20, a negative regulator of the NF-kappa B 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-kappa B-mediated activation of A20 promoter. In turn, A20 blocked K13-induced NF-kappa B activity and up-regulation of pro-inflammatory 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-kappa B activity. Overexpression of A20 blocked K13-induced I kappa B alpha phosphorylation, NF-kappa B nuclear translocation, and cellular transformation. Consistent with the above, K13-induced I kappa B alpha phosphorylation and NF-kappa B 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-kappa B activity. A20 might serve to control the inflammatory response to KSHV infection and protect KSHV-infected cells from apoptosis.

• 出版日期2011-6-17