title: Proinflammatory cytokine TNF-α increases the stability of hepatitis B virus X protein through NF-κB signaling.
abstract: 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.
authors: Infections and Cancer Biology Group, International Agency for Research on Cancer, 150 cours Albert-Thomas, 69372 Lyon Cedex 08, France.
authors: Ruchi
authors: R
authors: Shukla
authors: Jiping
authors: J
authors: Yue
authors: Maha
authors: M
authors: Siouda
authors: Tarik
authors: T
authors: Gheit
authors: Olivier
authors: O
authors: Hantz
authors: Philippe
authors: P
authors: Merle
authors: Fabien
authors: F
authors: Zoulim
authors: Vladimir
authors: V
authors: Krutovskikh
authors: Massimo
authors: M
authors: Tommasino
authors: Bakary S
authors: BS
authors: Sylla
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D020868:Gene Silencing; D006801:Humans; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D015398:Signal Transduction; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein