Abstract

Virus infection activates the host’s innate immune responses, which is a very precise and complex biological process and will lead to the immediate transcription of type I interferon. The general transcriptional activator proteins such as IRF3, ATF2/c-Jun, and NF-κB can be induced to form a stable enhanceosome in the transcriptional regulatory region of IFN-β promoter. Several cellular factors have recently been reported to be involved in the transcriptional regulation of IFN-β under certain physiological conditions. Here, we identified four and a half LIM domains protein 2 (FHL2) as an interacting protein of the Human Cytomegalovirus (HCMV) replication-related protein UL84 and determined that FHL2 plays an architectural role in enhancing the transcription of IFN-β induced by HCMV infection and many other viruses. Firstly, after the virus binds to the host cell, the signal is transmitted to protein kinases, causing the cytoplasmic FHL2 to be phosphorylated and translocated into the nucleus. Then, the phosphorylated FHL2 promotes the formation of the transcription preinitiation complex (PIC) of the IFN-β promoter. Simultaneously, FHL2 is also crucial for the recruitment of TFIID to the TATA-box for initial transcription. Interestingly, during HCMV infection, HCMV replication-related protein UL84 was determined to interact with FHL2 to help the virus evade innate immune response and promote viral lytic origin ( ori Lyt) dependent DNA replication. Our results highlight the FHL2 as part of a signaling cascade during viral invasion, and its important regulatory effect in type I interferon synthesis, as well as provide theoretical support for the development of candidate anti-HCMV drugs acting specifically on a novel UL84 target. HCMV-encoded UL84 was originally identified as an essential protein for viral lytic origin ( ori Lyt)-dependent DNA replication. In this study, we provided the first evidence that UL84, as a dual-functional protein, can also suppress host inna