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.
J Biol Chem. 2011 Jun 17;286(24):21555-64. doi: 10.1074/jbc.M111.224048. Epub 2011 Apr 29.
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.
A20 的表达，NF-κB 通路的负调节剂，在几种霍奇金和非霍奇金淋巴瘤亚型中经常丢失。我们报告 A20 在卡波西肉瘤相关疱疹病毒（KSHV）感染的原发性渗出性淋巴瘤细胞系中表达，其表达与 KSHV 编码的病毒 FLICE 抑制蛋白 K13 的表达密切相关。K13 的异位表达通过 NF-κB 介导的 A20 启动子激活诱导 A20 的表达。反过来，A20 通过负反馈方式阻断 K13 诱导的 NF-κB 活性和促炎细胞因子 CCL20 和 IL-8 的上调。A20 的 N 端去泛素化结构域和 C 端锌指结构域均参与抑制 K13 诱导的 NF-κB 活性。A20 的过表达阻断了 K13 诱导的 IκBα 磷酸化、NF-κB 核易位和细胞转化。与上述结果一致，A20 缺陷细胞中 K13 诱导的 IκBα 磷酸化和 NF-κB 转录激活增强。最后，发现 A20 与 K13 物理相互作用。总的来说，这些结果表明 K13 是 KSHV 感染细胞中 A20 表达的关键决定因素，A20 是 K13 诱导的 NF-κB 活性的关键负调节剂。A20 可能有助于控制对 KSHV 感染的炎症反应并保护 KSHV 感染的细胞免于凋亡。
