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

Hyesung Lee,Jinu Lee,Eun Ju Choi,Taek-Yeol Jung,Seong Hun Lim,Do Sik Min

doi:10.1038/s12276-021-00659-y

Hyesung Lee, Jinu Lee + Show 4 more

Open Access

https://doi.org/10.1038/s12276-021-00659-y

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Abstract

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.

Highlights

Sirtuins (SIRTs) belong to a family of class III histone deacetylases (HDACs) that is composed of seven mammalian members of SIRTs (SIRT1–7) with a conserved catalytic core for which nicotinamide adenine dinucleotide (NAD+) is a cofactor[1,2,3]
The LXXLL motifs are conserved among phospholipase D2 (PLD2) isozymes, and PLD2 but not PLD1 selectively interacts with Sirtuin 1 (SIRT1) Since the LXXLL motif is involved in the interaction with Phospholipase D (PLD) partner proteins, such as Sirt[122], we examined whether PLD isozymes contain LXXLL motifs
We identified two LXXLL motifs at amino acids 120–124 and 170–174 in human PLD2, which are highly conserved among PLD2 in mice, horses, chimpanzees, and cattle (Fig. 1a)

Summary

Introduction

Sirtuins (SIRTs) belong to a family of class III histone deacetylases (HDACs) that is composed of seven mammalian members of SIRTs (SIRT1–7) with a conserved catalytic core for which nicotinamide adenine dinucleotide (NAD+) is a cofactor[1,2,3]. Sirt[1] regulates a wide range of cellular functions, including cell survival, senescence, aging, differentiation, and metabolism, through its deacetylation activity targeting numerous transcription factors. These transcription factors include p53, forkhead box O3 (FoxO3), nuclear factor-κB, and peroxisome proliferator‐activated receptor gamma coactivator‐1α4. The molecular mechanisms that govern substrate selection by SIRT1 and the regulation of its deacetylation activity remain poorly defined. Both positive and negative regulations of Sirt[1] activity have therapeutic implications against some diseases, including aging, diabetes, and tumors[10]. The SIRT protein family is important because of its seemingly dichotomous role in cancer biology, with both tumor promoter and tumor suppressor functions in different cancers

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