Proinflammatory cytokine TNF-α increases the stability of hepatitis B virus X protein through NF-κB signaling

Ruchi Shukla, Jiping Yue, Maha Siouda, Tarik Gheit, Olivier Hantz, Philippe Merle, Fabien Zoulim, Vladimir Krutovskikh, Massimo Tommasino, Bakary S. Sylla*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)


Hepatitis B virus (HBV) X protein (HBx) is a key player in HBV-induced hepatocellular carcinoma (HCC). HBx interacts with several cell signaling molecules, leading to activation of various transcription factors including nuclear factor-kappaB (NF-κB). Activated NF-κB signaling is implicated in many human cancers including HCC. Here, we present evidence that the NF-κB signaling activator, tumor necrosis factor (TNF)-α, induces the accumulation of HBx in cells by increasing protein stability due to reduced proteasomal degradation. The effects of TNF-α on HBx protein stability are mediated via activated NF-κB effector kinases IKKα and IKKβ and p65. The non-IKK-phosphorylable p65-S534A mutant did not induce HBx protein stability; hence, phosphorylation of p65 by IKK is a key step in TNF-α-induced stabilization of HBx. Phospho-p65 showed higher affinity to HBx compared with the non-phosphorylable p65 mutant, suggesting that the interaction of phospho-p65 with HBx might be important for HBx stabilization. We also show that the increased level of HBx in cells cooperates with TNF-α toward activation of NF-κB and expression of NF-κB-regulated genes, indicating a positive feedback loop between HBx and NF-κB signaling. Overall, our study provides evidence for interplay between HBx and NF-κB signaling, which may account for HBV-mediated liver carcinogenesis.

Original languageEnglish
Pages (from-to)978-985
Number of pages8
Issue number7
Publication statusPublished - 1 Jul 2011
Externally publishedYes


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