Abstract
Bromodomain-containing protein 2 (BRD2) is a nucleus-localized serine-threonine kinase that plays pivotal roles in the transcriptional control of diverse genes. In our previous study, the chicken BRD2 (chBRD2) protein was found to interact with the Newcastle disease virus (NDV) matrix (M) protein using a yeast two-hybrid screening system, but the role of the chBRD2 protein in the replication of NDV remains unclear. In this study, we first confirmed the interaction between the M protein and chBRD2 protein using fluorescence co-localization, co-immunoprecipitation and pull-down assays. Intracellular binding studies indicated that the C-terminus (aa 264–313) of the M protein and the extra-terminal (ET) domain (aa 619–683) of the chBRD2 protein were responsible for interactions with each other. Interestingly, although two amino acids (T621 and S649) found in the chBRD2/ET domain were different from those in the human BRD2/ET domain and in that of other mammals, they did not disrupt the BRD2-M interaction or the chBRD2-M interaction. In addition, we found that the transcription of the chBRD2 gene was obviously decreased in both NDV-infected cells and pEGFP-M-transfected cells in a dose-dependent manner. Moreover, small interfering RNA-mediated knockdown of chBRD2 or overexpression of chBRD2 remarkably enhanced or reduced NDV replication by upregulating or downregulating viral RNA synthesis and transcription, respectively. Overall, we demonstrate for the first time that the interaction of the M protein with the chBRD2 protein in the nucleus promotes NDV replication by downregulating chBRD2 expression and facilitating viral RNA synthesis and transcription. These results will provide further insight into the biological functions of the M protein in the replication of NDV.
Highlights
Newcastle disease (ND) is an important avian infectious viral disease that causes neurological, respiratory, and gastrointestinal symptoms in poultry and may lead to devastating losses in the poultry industry worldwide [1]
Regarding paramyxovirus M protein and host protein interactions, it has been reported that the interaction of the Nipah and Hendra virus M proteins with AP3B1 protein promotes virus-like particle (VLP) production [33]
The angiomotin-like 1 protein interacts with the parainfluenza virus 5 (PIV5) M protein [34] and acts as a linker between the PIV5 M and NEDD4 ubiquitin ligases [35], which reveals a novel host factor recruitment strategy for paramyxoviruses to achieve VLP production and virus budding
Summary
Newcastle disease (ND) is an important avian infectious viral disease that causes neurological, respiratory, and gastrointestinal symptoms in poultry and may lead to devastating losses in the poultry industry worldwide [1]. The causative agent of ND is Newcastle disease virus (NDV), known as avian paramyxovirus type 1, which. Like the M protein of most paramyxoviruses, the NDV M protein is a multifunctional nucleocytoplasmic trafficking protein [6]. Recent studies have shown that nuclear-cytoplasmic trafficking of the NDV M protein is mediated by its intrinsic nuclear localization signal (NLS) and nuclear export signals (NESs) [11, 12]. M/NLS mutation results in a pathotype change of NDV and attenuates viral replication and pathogenicity [11], while M/NES mutation causes ineffective rescue of NDV [12], demonstrating that nucleocytoplasmic trafficking of the NDV M protein plays crucial roles in the virus life cycle
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