Virus infection may affect the epigenetic regulations in host cells, including post-translational histone modifications. Ubiquitination of histone H2B, has been reported to be involved in transcription activation. However, it remains unknown the role of histone ubiquitination in the pathology of virus infection (e.g. influenza virus, SARS-CoV2). CNOT4 that is a component of the CCR4-NOT complex has a ubiquitin transferase activity at the RING domain (L16). Here we show that CNOT4 is responsible for histone H2B ubiquitination in the host cells, which was linked to H3K4 methylation. Upon influenza virus or SARS-CoV2 virus infection CNOT4 interacted to virus protein, resulting in the loss of H2B ubiquitination and H3K4 methylation, which suppress interferon-related gene expression. The cells with a ubiquitination activity site of L16 of CNOT4, have increased virus replication. These results suggest that the CNOT4 is involved in the virus replication through histone H2B ubiquitination.