Regulation of Mumps Virus Replication and Transcription by Kinase RPS6KB1

Abstract

Mumps virus (MuV) caused the most viral meningitis before mass immunization. Unfortunately, MuV has reemerged in the United States in the past several years. MuV is a member of the genus Rubulavirus, in the family Paramyxoviridae, and has a nonsegmented negative-strand RNA genome. The viral RNA-dependent RNA polymerase (vRdRp) of MuV consists of the large protein (L) and the phosphoprotein (P), while the nucleocapsid protein (NP) encapsulates the viral RNA genome. These proteins make up the replication and transcription machinery of MuV. The P protein is phosphorylated by host kinases, and its phosphorylation is important for its function. In this study, we performed a large-scale small interfering RNA (siRNA) screen targeting host kinases that regulated MuV replication. The human kinase ribosomal protein S6 kinase beta-1 (RPS6KB1) was shown to play a role in MuV replication and transcription. We have validated the role of RPS6KB1 in regulating MuV using siRNA knockdown, an inhibitor, and RPS6KB1 knockout cells. We found that MuV grows better in cells lacking RPS6KB1, indicating that it downregulates viral growth. Furthermore, we detected an interaction between the MuV P protein and RPS6KB1, suggesting that RPS6KB1 directly regulates MuV replication and transcription. IMPORTANCE Mumps virus is an important human pathogen. In recent years, MuV has reemerged in the United State, with outbreaks occurring in young adults who have been vaccinated. Our work provides insight into a previously unknown mumps virus-host interaction. RPS6KB1 negatively regulates MuV replication, likely through its interaction with the P protein. Understanding virus-host interactions can lead to novel antiviral drugs and enhanced vaccine production.

Molecular mechanisms of stress-induced reactivation in mumps virus condensates

“…The intracellular levels of many kinases and phosphatases changed under stress ( STAR Methods ). However, the enzymes responsible for P phosphorylation 65 , 66 need further investigation, with changes in the activity of the enzymes considered alongside their abundance. Second, we observed that the magnitude of increase in replication activity correlated with the severity of stress: genomic RNA level under mild As(III) stress was slightly suppressed until 6 h before showing a dramatic upregulation at 24 h, reminiscent of acute phase infection where transcription is prioritized to generate more material (e.g., polymerase and nucleocapsid protein) required for replication.…”

Molecular docking study of Zingiber officinale Roscoe compounds as a mumps virus nucleoprotein inhibitor

“…These proteins have important roles as transcription and replication machines in MuV. 6 NP protein in MuV plays a role in the formation of the vRNA complex to avoid degradation and initiate the replication process. Inhibition of the NP protein's activity will disturb the initiation of the replication process through an increase of degradation of vRNA in MuV.…”

“…These proteins have important roles as transcription and replication machines in MuV. 6 The template that initiates the replication and synthesis of MuV comes from the RNA genome virus (vRNA). Subsequently, vRNA can establish a complex with NP that generates helix-shaped proteins or ribonucleoproteins (RNPs) to avoid degradation.…”

Borna Disease Virus 1 Phosphoprotein Forms a Tetramer and Interacts with Host Factors Involved in DNA Double-Strand Break Repair and mRNA Processing

“…It also chaperones N to maintain it in an RNA-free form needed for replication [21][22][23][24][25][26][27][28]. In addition, P is an essential actor of viral replication by recruiting a plethora of cellular partners with proviral activities [10,[29][30][31][32][33][34][35][36][37][38][39][40]. The disordered regions of P seem to be of primary importance for these additional functions.…”