Abstract
The regulation of paramyxovirus RNA synthesis by host proteins is poorly understood. Here, we identified a novel regulation mechanism of paramyxovirus RNA synthesis by the Hsp90 co-chaperone R2TP complex. We showed that the R2TP complex interacted with the paramyxovirus polymerase L protein and that silencing of the R2TP complex led to uncontrolled upregulation of mumps virus (MuV) gene transcription but not genome replication. Regulation by the R2TP complex was critical for MuV replication and evasion of host innate immune responses. The R2TP complex also regulated measles virus (MeV) RNA synthesis, but its function was inhibitory and not beneficial to MeV, as MeV evaded host innate immune responses in the absence of the R2TP complex. The identification of the R2TP complex as a critical host factor sheds new light on the regulation of paramyxovirus RNA synthesis.
Highlights
Many human and animal pathogens are members of the family Paramyxoviridae [1], including mumps rubulavirus (MuV) and measles morbillivirus (MeV)
We identified the R2TP complex as a novel host factor regulating paramyxovirus RNA synthesis
We showed that the R2TP complex precisely regulated mumps virus (MuV) transcription by interacting with the polymerase L protein
Summary
Many human and animal pathogens are members of the family Paramyxoviridae [1], including mumps rubulavirus (MuV) and measles morbillivirus (MeV). Mumps is a common childhood illness characterized by painful swelling of the parotid glands, and is often accompanied by severe complications such as orchitis, aseptic meningitis, pancreatitis and deafness [2]. In addition to the terminal control regions, transcriptional control sequences exist at the beginning and end of each gene. The viral genome forms ribonucleoprotein (RNP) complexes with the nucleocapsid (N) protein and the RNA-dependent RNA polymerase (RdRp), which is composed of the large (L) protein and the phosphoprotein (P) [1]. The RNP complex, but not the naked genome, functions as an active template for both transcription and genome replication. RdRp initiates transcription from the 3’ end of the genome, and transcribes viral genes in sequential order [8]. Since RdRp may dissociate from the genome at the boundaries between each gene, mRNAs derived from 3’ genes are always more abundant than those of 5’ genes, producing a transcriptional gradient of mRNA abundance [8,9]
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