Mechanisms for human cytomegalovirus-induced cytoplasmic p53 sequestration in endothelial cells

Abstract

endothelial dysfunction, typically known as dysregulated apoptosis, and aberrant expression and sub-cellular localization of p53, a tumor suppressor that accumulates at the late stage of infection. In this study, we examined three hypotheses that could be responsible for HCMV-induced cytoplasmic p53 accumulation at the later stage of infection: hyperactive nuclear export, cytoplasmic p53 tethering and delayed p53 degradation. Leptomycin B treatment, a nuclear export inhibitor, was unable to reduce cytoplasmic p53, thereby eliminating the hyperactive nuclear export mechanism. The findings that nascent p53 still entered nuclei after the nuclear export inhibition indicated that cytoplasmic tethering may play a minor role.Cytoplasmic p53 was still observed after the translation activities were blocked by cycloheximide. There was more than an eight-fold increase in the cytoplasmic p53 half-life with abnormal p53 ubiquitination. Taken together, these results suggest that delayed degradation could be responsible for the cytoplasmic p53 accumulation. The general slow-down of the proteasomal activity and the dysregulated p53 ubiquitination process at the later stage of infection could contribute to the reduced cytoplasmic p53 degradation and might be relevant to dysregulated endothelial apoptosis. The HCMV-induced changes in p53 dynamics could contribute to endothelial dysfunction.

Assessment of Peripheral Endothelial-Dependent Vasodilatation Within the First Year After Heart Transplantation

“…28 CMV infection induces a pro-inflammatory state and has been associated with endothelial damage. 35,36 Despite CMV tropism for endothelial cells, no differences were documented in peripheral FMD between patients with or without CMV infection in the current study. Nevertheless, coronary ED due to CMV infection is probably more relevant than peripheral ED.…”

Cytoplasmic Translocation of p53 by Human Cytomegalovirus Infection

“…Cytoplasmic sequestration of p53 after HCMV infection was also reported in endothelial cells (16,20,21). mRNA of p53 decreased and maintained at a low level after HCMV infection (Fig.…”

“…Besides transcriptional regulation p53 facilitates the transportation of one of HCMV matrix proteins from nucleus to cytoplasm and induces the production of viruses (15). The sequestration of p53 was reported in the cytoplasm of endothelial cells after HCMV infection (16). Although the interactions of p53 with some HCMV proteins such as HCMV major capsid protein (MCP, UL86), UL25, pp65 (UL83), and UL44 were reported by our previous work (14), the mechanism of p53 exportation to the cytoplasm are not fully elucidated.…”

TGF-β and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3

“…S2). Phosphorylation is known to induce cellular compartment transitions for other transcription factors (37,38). Although we have noted acetylation of FOXP3, we are aware and show that histone modifications are also dominantly affected by acetylation.…”