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细胞信号转导异常可揭示人类疾病发生的本质,一些病毒的致病机制即源于其蛋白所致宿主细胞内信号转导的紊乱。丙型肝炎病毒(HCV)感染是引起人类严重肝脏疾病的主要病因,但致病机制尚未明确。HCV包膜蛋白2(E2蛋白)能介导病毒吸附并结合至靶细胞表面,此乃HCV感染的前提及首发事件。推测HCV E2蛋白经与其受体(人CD81)的相互作用而将病毒感染信号传递至宿主细胞内,使细胞增殖和分化异常,从而导致感染细胞发生早期病变。为进一步验证此致病机制,研究了HCV E2蛋白等诸因素对差异表达人CD81的U937,Molt-4细胞内MAPK/ERK途径的影响,结果表明,HCVE2蛋白可特异性激活细胞内MAPK/ERK途径,而HCV E2单抗、CD81单抗、慢性HCV感染患者血清或MAPK/ERK途径上游MEK1的抑制剂(PD98059)均不同程度地减弱或抑制HCV E2蛋白对MAPK/ERK的激活。此外,PD98059尚可抑制HCV E2蛋白对MAPK/ERK途径下游转录因子Elk-1的活化。研究认为,HCV E2蛋白经其相应受体引发的宿主细胞跨膜信号转导异常很可能是HCV的致病机制之一。
Abnormal cell signal transduction can reveal the nature of human diseases, some of the pathogenesis of the virus that is derived from its protein-induced signal transduction disorder in host cells. Hepatitis C virus (HCV) infection is the leading cause of severe liver disease in humans, but the pathogenesis is not yet clear. HCV envelope protein 2 (E2 protein) mediates viral attachment and binds to the surface of target cells, a prerequisite and first episode of HCV infection. It is speculated that the HCV E2 protein, through its interaction with its receptor (human CD81), signals viral infection to the host cells, causing abnormal proliferation and differentiation of the cells, resulting in early lesions in the infected cells. To further verify the mechanism of this disease, we studied the effects of HCV E2 protein and other factors on MAPK / ERK pathway in human CD81-differentially expressed U937 and Molt-4 cells. The results showed that HCVE2 protein can specifically activate intracellular MAPK / ERK , Whereas HCV E2 monoclonal antibody, CD81 monoclonal antibody, serum of patients with chronic HCV infection or MEK1 inhibitor upstream of MAPK / ERK pathway (PD98059) attenuated or inhibited the activation of MAPK / ERK by HCV E2 protein. In addition, PD98059 still inhibits the activation of Elk-1, a transcription factor downstream of the MAPK / ERK pathway, by the HCV E2 protein. It is concluded that the abnormal transduction of host cell transmembrane signal transduction by HCV E2 protein via its corresponding receptor is likely to be one of the pathogenesis of HCV.