Phospholipase D2 is a positive regulator of sirtuin 1 and modulates p53-mediated apoptosis via sirtuin 1

• Published in: Experimental & molecular medicine 2021, 53(0), , pp.1-11
• Main Authors: Lee, Hyesung, Jung, Taek-Yeol, Lim, Seong Hun, Choi, Eun Ju, Lee, Jinu, Min, Do Sik
• Format: Article
• Language: English
• Subjects: 631/67/2327; 631/80/86/2365; 96/2; Adenine; Amino Acid Motifs; Amino Acid Sequence; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biomedical and Life Sciences; Biomedicine; Cell death; Chemotherapy; Deacetylation; Enzyme Activation; Enzymes; Etoposide; Etoposide - pharmacology; Gene Expression Regulation; Genes, Reporter; Genotoxicity; Histone deacetylase; Humans; Isoenzymes; Medical Biochemistry; Molecular Medicine; Mutagenesis; NAD; p53 Protein; Phospholipase D - chemistry; Phospholipase D - metabolism; Phospholipase D2; Protein Binding; Protein Interaction Domains and Motifs; Signal Transduction; SIRT1 protein; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Stem Cells; Tumor cells; Tumor Suppressor Protein p53 - metabolism; Tumors; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-021-00659-y

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent histone deacetylase that plays diverse physiological roles. However, little is known about the regulation of SIRT1 activity. Here, we show that phospholipase D2 (PLD2), but not PLD1, selectively interacts with SIRT1 and increases the deacetylase activity of SIRT1. PLD2 does not interact with the other isozymes of SIRT (SIRT2–7). Two leucine residues in the LXXLL motif (L173 and L174) in the phox domain of PLD2 interact with the region essential for SIRT1 activity. PLD2 stimulates the SIRT1-mediated deacetylation of p53 independent of its lipase activity. In our study, mutagenesis of the LXXLL motif suppressed the interaction of PLD2 with SIRT1 and inhibited SIRT1-mediated p53 deacetylation and p53-induced transactivation of proapoptotic genes. Ultimately, overexpression of wild-type PLD2 but not that of LXXLL-mutant PLD2 protected cells against etoposide-induced apoptosis. Moreover, PLD2 did not protect against apoptosis induced by SIRT1 depletion under genotoxic stress. Collectively, our results suggest that PLD2 is a positive regulator of SIRT1 and modulates p53-mediated apoptosis via SIRT1. Cancer: Regulating tumor cell self-defense New details about the regulatory mechanisms that prevent tumor cell death could be exploited to increase the effectiveness of chemotherapy. The sirtuin (SIRT) protein family has been linked to both promotion and suppression of tumors in different cancers. The enzyme SIRT1 in particular deacetylates, and thereby deactivates, the key tumor-suppressing antigen p53, stopping p53 from inducing apoptosis (controlled cell death) in tumors. Do Sik Min at Yonsei University, Incheon, South Korea, and co-workers revealed that this SIRT1 deacetylation of p53 is greatly enhanced by the activity of the enzyme phospholipase D2 (PLD2). A particular region on PLD2 is required to activate SIRT1, this activation leading to protection of tumor cells from apoptosis induced by the chemotherapy drug etoposide. Therapies that target that region on PLD2 might therefore suppress a tumor’s natural resistance to chemotherapy.