HBV is a small DNA virus that induces acute and chronic liver diseases. Chronic hepatitis B is a major health problem since more than 50 % of HCC cases worldwide are related to HBV infection (HCC). Despite strong epidemiological evidence linking HBV infection to HCC, the mechanisms underlying HBV-associated carcinogenesis remain an open question (Neuveut et al, 2010 J Hepatol.). The HBV-encoded HBx oncoprotein is a multi-functional regulator of transcription and signal transduction that is essential for HBV replication and is thought to contribute to hepatocarcinogenesis. HBx that acts as a co-factor in oncogenesis may participate in cell transformation in several ways. Indeed, in order to favor virus replication, HBx has been shown to subvert cellular activities such as signal transduction, transcription and proliferation. Among the different activities of HBx, its transactivation function is believed to be crucial for viral replication and in the development of liver cancer. However the molecular mechanisms underlying this activity is yet not fully understood. In order to uncover molecular mechanism underlying HBx transcriptional activity, we searched for HBx interacting partner using purification affinity. We identified the cellular protein Spindlin1 and showed that it is recruited to the cccDNA and involved in cccDNA silencing. We observed that Spindlin1 knockdown correlates with HBV cccDNA transcription and with increase of H3K4me3 on the cccDNA suggesting that spindlin1 could impact on chromatin modifications. In the setting of infection, we also found that Spindlin1 represses the transcription of Herpes Simplex Virus type 1, a DNA virus that also replicate in the nucleus. Our study identifies for the first time Spindlin1 as a cellular protein involved in the intrinsic antiviral response (Ducroux et al., Plos Path. 2014).
Spindlin1 is a cellular protein that contains three Tudor-like domains. While its functions in the cell are not yet understood, it may be involved in transcriptional regulation. Spindlin1 has been shown to be recruited on cellular promoters and activates transcription via the simultaneous recognition of H3K4me3 and asymmetric H3R8 dimethylation through its Tudor domain 1 and 2 respectively. The mechanism leading to transcriptional activation remains however unknown.
Our project aims at deciphering the role and the molecular mechanisms of Spindlin1 in the transcriptional repression of the cccDNA and in HBx-induced hepatocarcinogenesis.