The ARTS of p53-dependent mitochondrial apoptosis

Abstract

The tumor-suppressive activity of p53 is largely attributed to its ability to induce cell death, including apoptosis, through transcription-dependent and transcription-independent mechanisms. On the one hand, nuclear p53 transcriptionally activates the expression of a myriad of pro-apoptotic BCL-2 family genes, such as NOXA, PUMA, BID, BAD, BIK, BAX, etc., whereas it inactivates the expression of anti-apoptotic BCL-2, BCL-XL, and MCL1, leading to mitochondrial apoptosis. On the other hand, cytoplasmic p53 also promotes mitochondrial apoptosis by directly associating with multiple BCL-2 family proteins in the mitochondria. Apoptosis-related protein in TGF-β signaling pathway (ARTS), a mitochondria-localized pro-apoptotic protein encoded by an alternative spliced variant of the SEPT4 gene, triggers apoptosis by facilitating proteasomal degradation of BCL-2 and XIAP upon pro-apoptotic stimuli. We recently identified SEPT4/ARTS as a new p53 target gene in response to genotoxic stress. ARTS in turn binds to p53, drives its mitochondrial localization, and enhances the interaction between p53 and BCL-XL, thereby promoting mitochondrial apoptosis. This review will illustrate the mechanisms of p53-induced mitochondrial apoptosis, offer some recently discovered new insights into the functions of ARTS in regulating mitochondrial cell death, and discuss the clinical significance of ARTS in cancer and non-cancer diseases.

Keywords: ARTS; BCL-2 family; SEPT4; apoptosis; cancer therapy; p53.

Figure 1

p53-dependent mitochondrial apoptotic signaling network. Nuclear p53 transcriptionally activates the expression of PUMA, NOXA, BID, BAD, BIM, BIK, BAX, and APAF1, but represses the expression of BCL-2, BCL-X_L, and MCL1. In addition, p53 may induce BMF expression through the FBXW7–YTHDF2 cascade. With the aid of ARTS, MDMX, and PTMs, cytoplasmic p53 can translocate to the mitochondria to interact with BAX, BAK, BCL-2, BCL-X_L, and MCL1, consequently inducing apoptosis.

Figure 2

The role of ARTS in promoting mitochondrial apoptosis. ARTS is encoded by a p53-target gene whose expression is responsive to diverse apoptotic stimuli, such as DNA damage stress and TGF-β activation. There are three mechanisms for ARTS-induced mitochondrial apoptosis: (i) ARTS facilitates the mitochondrial localization of p53 and enhances the p53–BCL-X_L interaction at the mitochondria; (ii) ARTS suppresses XIAP and promotes its proteasomal degradation by recruiting SIAH1 as a ternary complex; and (iii) ARTS bridges BCL-2 and XIAP by directly binding to them, allowing for XIAP-mediated proteasomal degradation of BCL-2.