Hepatitis C Virus NS5A Targets the Nucleosome Assembly Protein NAP1L1 to Control the Interferon Response

Hepatitis C virus (HCV) is a hepatotropic virus affecting more than 150 million people worldwide. HCV establishes a chronic infection in the majority of cases, which leads to severe liver complications such as cirrhosis and hepatocellular carcinoma. Fortunately, recent potent direct acting antivirals can now cure the infection. However, such treatments can induce resistance, are extremely costly limiting their use to wealthier countries and are ineffective for the complications of the infection. Therefore, a better understanding of the interaction of HCV with the host cell remains a priority both to increase the armamentarium of antiviral drugs and to define the relationship between infection and malignant transformation. My study focuses on the mechanisms governing the evasion of the innate immune system, which are required to establish a chronic infection. The non-structural viral protein NS5A has the capacity to interact with a large number of cellular factors involved in promoting viral replication/assembly and in the cell antiviral response to HCV. Interaction of NS5A with the nucleosome assembly protein NAP1L1 has been recently characterized in my laboratory. NAP1L1 is a histone chaperone protein with various functions related to nuclear chromatin remodelling that impact on the regulation of cell cycle, on cell differentiation and on transcription. I have confirmed the interaction of NS5A with NAP1L1 in the cytoplasm and demonstrated the NS5A-dependent impairment of NAP1L1 nuclear translocation. Whole genome transcription analysis performed in NAP1L1 depleted hepatocytes indicated that its nuclear function might be essential for the transcriptional control of several interferon stimulated genes and the function of key innate immunity pathways. Indeed, I was able to demonstrate that NAP1L1 is a novel factor involved in the interferon response and specifically modulates TBK1/IKKε mediated IRF-3 phosphorylation and NF-κB levels. Hence, both the TLR3 and RIG-I/MDA5 pathways are affected by NAP1L1 depletion. I could further demonstrate that NAP1L1 controls the basal transcription of genes involved in the immune pathway and that it interacts with the adaptor protein MAVS, which is required for RIG-I/MDA5 signalling. In conclusion, by studying the interaction of the viral protein NS5A with the cellular factor NAP1L1 I could discover a novel mechanism of regulation of the innate response mediated by NAP1L1. These findings have wider implications for HCV and beyond, further highlighting the importance of studying viruses to uncover cellular functions.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

The Open University

Year dc:date.issued

2017

Author dc:creator

• Cesarec, Mia

Language dc:language

en