The Wheel of p53 Helps to Drive the Immune System

Abstract

The p53 tumor suppressor protein is best known as an inhibitor of the cell cycle and an inducer of apoptosis. Unexpectedly, these functions of p53 are not required for its tumor suppressive activity in animal models. High-throughput transcriptomic investigations as well as individual studies have demonstrated that p53 stimulates expression of many genes involved in immunity. Probably to interfere with its immunostimulatory role, many viruses code for proteins that inactivate p53. Judging by the activities of immunity-related p53-regulated genes it can be concluded that p53 is involved in detection of danger signals, inflammasome formation and activation, antigen presentation, activation of natural killer cells and other effectors of immunity, stimulation of interferon production, direct inhibition of virus replication, secretion of extracellular signaling molecules, production of antibacterial proteins, negative feedback loops in immunity-related signaling pathways, and immunologic tolerance. Many of these p53 functions have barely been studied and require further, more detailed investigations. Some of them appear to be cell-type specific. The results of transcriptomic studies have generated many new hypotheses on the mechanisms utilized by p53 to impact on the immune system. In the future, these mechanisms may be harnessed to fight cancer and infectious diseases.

Keywords: immunity; negative-feedback loops; p53; transcriptome; virus.

Figure 1

Schematic representations of various p53 forms generated by posttranslational modifications induced by stress factors encountered by cells. Activated p53 stimulates expression of a set of genes regardless of the type of stress (common target genes), whereas other genes (stress-specific genes) are preferentially activated only when p53 is modified in a particular fashion. While common target genes are well known, the stress-specific genes are not well recognized. P53 modifications induced by infections have been poorly studied. Created with BioRender.com (accessed on 14 February 2023).

Figure 2

Immune-related processes regulated by p53 through activation of the indicated genes. The list of genes is far from complete, partly because p53 regulates expression of many genes with unknown function, which potentially may participate in immunity. Regulation of some genes by p53 is well-documented, whereas the involvement of p53 in regulation of other genes is only currently being discovered—see text. Created with BioRender.com (accessed on 14 February 2023).

Figure 3

The involvement of p53 in activation of interferon genes, of interferon-stimulated genes, and in feedback loops regulating these processes. Red arrows mark the genes positively regulated by p53. ISRE—interferon-stimulated response element, a DNA sequence that confers responsiveness to type I interferons. GAS—interferon-gamma-activated site, a DNA sequence element through which interferon gamma can activate transcription. For clarity, the signaling from toll-like receptors is oversimplified, e.g., some of them are localized in the cell membrane, whereas others are localized in the endosome membrane. The exact localization of GLIPR2 in this signaling pathway is not known. STING protein can also recognize foreign DNA in the cell nucleus. The entry method of viruses into cells is also only schematically represented. Adapted from “Interferon Pathway”, by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates accessed on 14 February 2023.