Virus-induced changes in cellular signaling in hepatocytes lead to reprogramming of the cell response to growth factors – analysis of molecular mechanisms and functional consequences

在以前的工作中，我们能够有助于更好地了解病毒病原体，如丙型肝炎病毒（HCV）或巨细胞病毒，与宿主的细胞内和细胞间信号转导相互作用的机制。这些研究不仅使我们对病毒-宿主相互作用有了新的认识，而且使我们对宿主中的信号转导以及改变信号中间体的活化对整个信号网络的影响有了新的认识。例如，通过病毒编码的蛋白酶NS3/4A，普遍表达的T细胞蛋白酪氨酸磷酸酶（TC-PTP）（EGF受体的重要内源性负调节剂）的蛋白水解降解不仅导致EGF受体的增强的活化性，而且导致蛋白激酶Akt的组成性活化。这表明TC-PTP间接控制Akt激酶活化。此外，我们证明，这大大有助于"重编程"的宿主细胞在其响应ErbB配体。例如，HCV引起ErbB受体家族成员的表面表达的广泛变化，并导致诱导几种ErbB配体如EGF、神经调节蛋白-1和调蛋白的表达，其中一些又激活自动调节反馈机制。这最终导致宿主细胞的趋化因子介导的细胞间通讯行为发生显著变化。是发展隐匿性但不减轻的肝脏炎症的重要因素的机制，其特征在于局部免疫或微环境的各种变化。由于大约90%的HCC病例是在慢性肝脏炎症的背景下发展的，因此可以合理地推测，与本文研究的肝细胞"重编程"相关的持续炎症反应在慢性炎症反应的背景下也在肝细胞的恶性转化中起重要作用。在这项研究中，我们希望进一步阐明肝炎病毒，如HBV和HCV影响ErbB配体在肝细胞中表达的调节的分子机制。此外，诱导这些不同的ErbB配体对宿主细胞中ErbB受体家族成员的表面表达的相互作用以及转录因子SP1和NF κ B的失调或增强的活化的重要性将被进一步研究。最后，将研究这种宿主细胞重编程对免疫细胞（如单核细胞衍生的巨噬细胞）的细胞间通讯和功能的影响，并鉴定与此相关的信号。

In previous work, we were able to contribute to a better understanding of the mechanisms by which viral pathogens, such as hepatitis C virus (HCV) or cytomegalovirus, interact with the intra- and intercellular signal transduction of the host. These studies led not only to new insights into virus-host interaction but also into signal transduction in the host and the effects of altering the activation of signaling intermediates on the overall signaling network. For example, proteolytic degradation of ubiquitously expressed T-cell protein tyrosine phosphatase (TC-PTP), an important endogenous negative regulator of the EGF receptor, by the virus-encoded protease NS3/4A leads not only to enhanced activability of the EGF receptor but also to constitutive activation of protein kinase Akt. This suggests that TC-PTP indirectly controls Akt kinase activation. Further, we demonstrated that this contributes substantially to "reprogramming" of the host cell in its response to ErbB ligands. For example, HCV elicits an extensive change in the surface expression of members of the ErbB receptor family and leads to the induction of the expression of several ErbB ligands such as EGF, neuregulin-1, and heregulin, some of which in turn activate auto-regulatory feedback mechanisms. This culminates in a significant change in the chemokine-mediated inter-cellular communication behavior of the host cell. Mechanisms that are essential contributors to the development of insidious, but not abating, liver inflammation characterized by a variety of changes in the local immune or microenvironment. Since approximately 90% of HCC cases develop in the context of chronic liver inflammation, it is reasonable to speculate that the ongoing inflammatory response associated with hepatocyte "reprogramming“ investigated herein also plays an important role in the malignant transformation of liver cells in the context of chronic inflammatory responses. In this study we would like to further elucidate the molecular mechanisms by which hepatitis viruses such as HBV and HCV influence the regulation of the expression of ErbB ligands in hepatocytic cells. Furthermore, the reciprocal effects of the induction of these different ErbB ligands on the surface expression of ErbB receptor family members in the host cell and the importance of the dysregulation or enhanced activation of the transcription factors SP1 and NFkB will be further investigated. Finally, the impact of this host cell reprogramming on intercellular communication with and function of immune cells such as monocyte-derived macrophages will be investigated and signals relevant in this context identified.