Hepatitis C virus core protein potentiates c-Jun N-terminal kinase activation through a signaling complex involving TRADD and TRAF2

The hepatitis C virus (HCV) core protein is a multifunctional viral nucleoc apsid protein. Previously, it has been demonstrated that the HCV core prote in interacts with the cytoplasmic domain of tumor necrosis factor receptor 1 (TNFR1). Since the TNFR1 is engaged in stimulation of transcriptional fac tor NF-kappaB and AP-I through activation of I kappaB kinase and c-Jun N-te rminal kinase (JNK, or stress-activated protein kinase), respectively, we h ave examined whether the interaction between core protein and TNFR1 can mod ulate JNK. In this study, we demonstrate that the HCV core protein synergis tically activates TNF alpha -induced JNK at a core concentration dependent manner in human embryonic kidney (HEK) 293 cells. HCV core-mediated synergi sm of JNK activation was also detected in stable cells expressing HCV core protein. Furthermore, we demonstrate that HCV core protein does not compete with TNF receptor-associated death domain (TRADD) for its interaction with the death domain of TNFR1. Our in vivo data show that HCV core and TRADD f orm a ternary complex with TNFR1. These findings suggest that the HCV core protein modulates TNFR1 signaling and may, thus, play a role in chronic inf ection of HCV patients. (C) 2001 Elsevier Science B.V. All rights reserved.