# PCBP2 inhibits antiviral innate immune responses via the MAVS-mediated signaling pathway in severe fever with thrombocytopenia syndrome

## TL;DR

PCBP2 weakens the body's antiviral immune response in a severe tick-borne disease, making it a potential treatment target.

## Contribution

PCBP2 is identified as a novel negative regulator of antiviral immunity in Dabie bandavirus infection via MAVS degradation.

## Key findings

- PCBP2 expression is reduced in SFTS and correlates with disease severity.
- PCBP2 promotes viral replication by degrading MAVS and inhibiting interferon signaling.
- PCBP2 is a potential host-directed therapeutic target for SFTS.

## Abstract

•PCBP2 is downregulated in SFTS and negatively correlates with disease severity.•PCBP2 suppresses DBV-triggered IFN-β and ISG production in human monocytes.•PCBP2 directly binds MAVS and induces its K48-linked polyubiquitination.•PCBP2 promotes DBV replication by degrading MAVS and inhibiting innate immunity.•PCBP2 is a potential therapeutic target for controlling SFTS virus infection.

PCBP2 is downregulated in SFTS and negatively correlates with disease severity.

PCBP2 suppresses DBV-triggered IFN-β and ISG production in human monocytes.

PCBP2 directly binds MAVS and induces its K48-linked polyubiquitination.

PCBP2 promotes DBV replication by degrading MAVS and inhibiting innate immunity.

PCBP2 is a potential therapeutic target for controlling SFTS virus infection.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease with high mortality and limited therapeutic options. Poly(rC)-binding protein 2 (PCBP2) is a multifunctional RNA-binding protein involved in post-transcriptional regulation and innate immune modulation. Although PCBP2 has been reported to negatively regulate antiviral signaling in other viral infections, its role in Dabie bandavirus (DBV) infection remains unclear.

Single-cell transcriptomic analysis was performed to characterize PCBP2 mRNA expression across immune cell populations in peripheral blood. PCBP2 expression levels were further examined in DBV-infected clinical samples, IFNAR⁻/⁻ mouse models, and THP-1 cells using quantitative RT-PCR, western blotting, and immunohistochemistry. THP-1 cells with plasmid-mediated PCBP2 overexpression or lentivirus-mediated PCBP2 knockdown were established to investigate the functional role of PCBP2. Activation of the RIG-I-like receptor (RLR) signaling pathway was evaluated by assessing key signaling molecules and downstream interferon responses. The impact of PCBP2 on DBV replication was determined by TCID50 assay, viral nucleoprotein (NP) expression, and immunofluorescence analysis.

PCBP2 expression was significantly downregulated during DBV infection in clinical samples, animal models, and cell cultures, and reduced PCBP2 expression was associated with increased disease severity and unfavorable clinical outcomes. Functional analyses demonstrated that PCBP2 suppressed DBV-induced activation of type I interferon signaling and interferon-stimulated genes, including ISG12a and G1P3. Mechanistically, PCBP2 directly interacted with the mitochondrial antiviral signaling protein MAVS and promoted its K48-linked polyubiquitination, resulting in proteasome-dependent degradation and attenuation of the MAVS-TBK1-IRF3 signaling axis. Consistent with its immunosuppressive role, PCBP2 knockdown significantly reduced DBV replication, whereas PCBP2 overexpression enhanced viral replication in THP-1 cells.

These findings identify PCBP2 as a critical negative regulator of RLR-mediated antiviral signaling during DBV infection. By facilitating MAVS degradation and suppressing innate immune responses, PCBP2 promotes viral replication, providing new insights into DBV immune evasion mechanisms and highlighting PCBP2 as a potential host-directed therapeutic target for SFTS.