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

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

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3 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1287-1297
Number of pages11
JournalExperimental and Molecular Medicine
Issue number9
Publication statusPublished - 2021 Sept

Bibliographical note

Funding Information:
The authors thank Dr. J. Kim (Kyung Hee University) for providing the SIRT1 deletion constructs. This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2018R1A2B3002179) and by the Yonsei University Research Fund of 2019-22-0193.

Publisher Copyright:
© 2021, The Author(s).

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry


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