Date Published: March 29, 2019
Publisher: Public Library of Science
Author(s): Shun Li, Long-Feng Lu, Shu-Bo Liu, Can Zhang, Zhuo-Cong Li, Xiao-Yu Zhou, Yong-An Zhang, Pinghui Feng.
p53, which regulates cell-cycle arrest and apoptosis, is a crucial target for viruses to release cells from cell-cycle checkpoints or to protect cells from apoptosis for their own benefit. Viral evasion mechanisms of aquatic viruses remain mysterious. Here, we report the spring viremia of carp virus (SVCV) degrading and stabilizing p53 in the ubiquitin-proteasome pathway by the N and P proteins, respectively. Early in an SVCV infection, significant induction was observed in the S phase and p53 was decreased in the protein level. Further experiments demonstrated that p53 interacted with SVCV N protein and was degraded by suppressing the K63-linked ubiquitination. However, the increase of p53 was observed late in the infection and experiments suggested that p53 was bound to SVCV P protein and stabilized by enhancing the K63-linked ubiquitination. Finally, lysine residue 358 was the key site for p53 K63-linked ubiquitination by the N and P proteins. Thus, our findings suggest that fish p53 is modulated by SVCV N and P protein in two distinct mechanisms, which uncovers the strategy for the subversion of p53-mediated host innate immune responses by aquatic viruses.
The tumor suppressor p53 is a crucial cellular stress sensor that triggers apoptosis, cell-cycle arrest, and a series life biology processes by responding to environmental stresses such as DNA damage, hyperproliferative signals, and hypoxia [1, 2]. The corresponding cellular responses mediated by p53 depend on its transcriptional factor role to induce particular target genes [3, 4]. The activity of p53 demands tight limitations to the cell’s stabilization and the protein level of p53 is low in normal cells [5–7]. Previous studies have indicated that p53 participates in the defense against viral infection depending on its capacity to activate cell-cycle arrest or apoptosis via the transcription of target genes [8–10]. p53-dependent apoptosis has been identified as a powerful control to restrict virus infection, such as by limiting the infections of vesicular stomatitis virus (VSV), influenza A virus (IAV), herpes simplex virus (HSV), and poliovirus [11–16]. A putative explanation is that early apoptosis would be harmful to the virus as they should use the host’s resources for replication, thus impairing the production of newly formed viral particles .
The battles between aquatic viruses and fish or other lower vertebrates have remained mysterious to date because knowledge about the molecular mechanisms regarding viral invasion, viral infection, host immune responses, and so on is insufficient. This study reports an aquatic virus called SVCV that employs two distinct manners to regulate the host key factor p53 expression, lowering p53 with N protein and increasing p53 with P protein to promote viral infection. Interestingly, our previous studies showed that SVCV N protein degraded host MAVS to blunt IFN production, and P protein acted as a decoy of TBK1 interfering with IRF3 phosphorylation to abrogate IFN transcription [28, 29]. Combined with these studies, SVCV N and P proteins play multidimensional roles in controlling cell fate and antagonizing the IFN system. Actually, considering that they are viral non-structure proteins, SVCV N and P proteins should also participate in viral genome transcription and replication like in other rhabdoviruses . This information indicates that two of the five viral proteins of SVCV possess multiple functions. That might be because, unlike DNA viruses, RNA viruses are usually composed of only a few proteins (e.g. SVCV only contains five proteins); hence, only efficient and multifunctional viral proteins are capable of accomplishing viral proliferation in host cells.