PEPD is a pivotal regulator of p53 tumor suppressor

Lu Yang,Yun Li,Arup Bhattacharya,Yuesheng Zhang

doi:10.1038/s41467-017-02097-9

Abstract

p53 tumor suppressor responds to various cellular stresses and regulates cell fate. Here, we show that peptidase D (PEPD) binds and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. Eliminating PEPD causes cell death and tumor regression due to p53 activation. PEPD binds to the proline-rich domain in p53, which inhibits phosphorylation of nuclear p53 and MDM2-mediated mitochondrial translocation of nuclear and cytoplasmic p53. However, the PEPD-p53 complex is critical for p53 response to stress, as stress signals doxorubicin and H2O2 each must free p53 from PEPD in order to achieve robust p53 activation, which is mediated by reactive oxygen species. Thus, PEPD stores p53 for the stress response, but this also renders cells dependent on PEPD for survival, as it suppresses p53. This finding provides further understanding of p53 regulation and may have significant implications for the treatment of cancer and other diseases.

Highlights

P53 tumor suppressor responds to various cellular stresses and regulates cell fate
We recently found that peptidase D (PEPD) is a ligand of ErbB1 and ErbB2 which are oncogenic receptor tyrosine kinases, that the enzymatic function of PEPD is not needed for this activity, and that intracellular PEPD has no effect on these receptors[8,9,10]
We have demonstrated that under normal conditions PEPD is essential for cell survival by suppressing p53

Summary

Introduction

P53 tumor suppressor responds to various cellular stresses and regulates cell fate. Here, we show that peptidase D (PEPD) binds and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. PEPD stores p53 for the stress response, but this renders cells dependent on PEPD for survival, as it suppresses p53. This finding provides further understanding of p53 regulation and may have significant implications for the treatment of cancer and other diseases. We recently found that PEPD is a ligand of ErbB1 and ErbB2 which are oncogenic receptor tyrosine kinases, that the enzymatic function of PEPD is not needed for this activity, and that intracellular PEPD has no effect on these receptors[8,9,10] It remains unclear about the physiological importance of PEPD as a ligand of ErbB1 and ErbB2 or the involvement of these receptors in PD, as circulating PEPD level is kept low by a plasma proteolysis pathway[11]. These findings uncover an important physiological function of PEPD and a critical new regulatory mechanism of p53

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