PEPD is a pivotal regulator of p53 tumor suppressor

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.

Current Understanding of the Emerging Role of Prolidase in Cellular Metabolism

“…Under silenced PEPD conditions, p53 phosphorylation at the Ser6 and Ser15 positions is promoted. The aforementioned findings prove that prolidase regulates both transcription-dependent and -independent functions of p53 [ 31 ].…”

“…In recent years, a new function of prolidase in p53 function has been discovered. PEPD is a key regulator of the key tumor suppressor protein [ 31 ]. The report reveals an important role in controlling cellular functions associated with the cell cycle, DNA repair, apoptosis, and cellular metabolism.…”

“…The regulation of the guardian of the genome is complex and still needs in-depth investigation. Among those mechanisms, prolidase also exhibits regulatory function on p53 through (1) limiting p53 subcellular transport and (2) inhibiting p53 phosphorylation [ 31 ].…”

“…Yang et al [ 31 ] demonstrated that PEPD regulates the activity of p53 through direct binding to this protein. They showed that PEPD catalytic domain is bound to the proline-rich domain of p53; however, PEPD motif binding to p53 is unknown.…”

“…In addition to its catalytic activity, prolidase regulates numerous biological processes. At the cellular level, PEPD acts as a regulator of epidermal growth factor receptor (EGFR) and epidermal growth factor receptor 2 (HER2)-dependent signaling pathways [ 26 , 27 , 28 , 29 , 30 ], p53 activity [ 31 ], and expression of the interferon α/β receptor [ 32 ].…”