# HCMV encoded UL84 hijacks FHL2 to suppress type I interferon production and enhance viral replication

## TL;DR

This study reveals how a virus protein, UL84, hijacks a host protein, FHL2, to suppress immune responses and boost viral replication.

## Contribution

The paper identifies UL84 as a dual-function protein that inhibits host immune responses by interacting with FHL2 during HCMV infection.

## Key findings

- FHL2 is phosphorylated and translocated to the nucleus after virus binding, promoting IFN-β transcription.
- UL84 interacts with FHL2 to disrupt IFN-β transcription and evade the host's innate immune response.
- Phosphorylated FHL2 facilitates the formation of the IFN-β enhanceosome complex.

## 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 thevirus 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 (oriLyt) 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 (oriLyt)-dependent DNA replication. In this study, we provided the first evidence that UL84, as a dual-functional protein, can also suppress host innate immune responses. Mechanistically, UL84 inhibits the transcription of IFN-β by competitively binding to FHL2, which disrupts the assembly of the transcription preinitiation complex and the recruitment of TBP. Meanwhile, we found that phosphorylation of FHL2 acts as part of a signaling cascade after virus-triggered and facilitates the formation of the IFN-β enhanceosome complex. The study highlights the novel function of HCMV-encoded UL84 in innate immune regulation and FHL2 as part of a signaling cascade during viral invasion, as well as its important regulatory effect in type I interferon synthesis. Therefore, candidate drugs targeting UL84 may not only inhibit HCMV replication but also enhance host immune responses.