# DNAJA2 inhibits Newcastle disease virus replication by targeting its V protein to modulate the MDA5-MAVS pathway

## TL;DR

DNAJA2 inhibits Newcastle disease virus replication by interacting with its V protein and boosting the immune response.

## Contribution

DNAJA2 is newly identified as a modulator of the MDA5-MAVS pathway through interaction with NDV V protein.

## Key findings

- DNAJA2 interacts with NDV V protein at residues 101–367 aa.
- DNAJA2 overexpression increases MDA5 and MAVS, leading to higher ISG and IFN-β production.
- DNAJA2 knockdown promotes NDV replication, while overexpression inhibits it.

## Abstract

As a molecular chaperone of heat shock protein 70 (HSP70), DnaJ heat shock protein family member A2 (DNAJA2) can facilitate protein folding under stress conditions and has recently emerged as a novel and critical regulator that modulates the innate immune response. The V protein of Newcastle disease virus (NDV) is a crucial virulence factor; however, its relationship with the heat shock protein family remains poorly understood.

We identified the interaction between DNAJA2 and NDV V proteins through immunoprecipitation‒mass spectrometry (IP‒MS) and confirmed that this interaction occurred mainly at residues 101–367 aa of DNAJA2. This finding was further validated by confocal microscopy and coimmunoprecipitation (co-IP). We found that the expression level of DNAJA2 is elevated during NDV infection. The overexpression of DNAJA2 enhances the expression of melanoma differentiation-associated gene 5 (MDA5) and mitochondrial antiviral signaling protein (MAVS), which upregulate the production of interferon-stimulated genes (ISGs) and interferon-β (IFN-β), thereby inhibiting the replication of NDV. In contrast, DNAJA2 knockdown promoted viral replication.

Notably, DNAJA2-mediated modulation of innate immunity occurred specifically in the presence of NDV or NDV V proteins, suggesting that DNAJA2 potentially activates immune signaling pathways by targeting the NDV V protein. These findings establish the role of DNAJA2 against NDV and combine the heat shock protein family with the innate immune pathway, providing new institutional insights into the relationship between the virus and the host and the prevention and control of the virus.

The online version contains supplementary material available at 10.1186/s12866-025-04618-9.