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.

Sirtuin 1 (SIRT1) 是一种烟酰胺腺嘌呤二核苷酸依赖性组蛋白脱乙酰酶，具有多种生理作用。然而，人们对 SIRT1 活性的调节知之甚少。在这里，我们显示磷脂酶 D2 (PLD2)，而不是 PLD1，选择性地与 SIRT1 相互作用并增加 SIRT1 的脱乙酰酶活性。PLD2 不与 SIRT 的其他同工酶 (SIRT2-7) 相互作用。PLD2 phox 结构域中 LXXLL 基序（L173 和 L174）中的两个亮氨酸残基与 SIRT1 活性所必需的区域相互作用。PLD2 刺激 SIRT1 介导的 p53 去乙酰化，与其脂肪酶活性无关。在我们的研究中，LXXLL 基序的诱​​变抑制了 PLD2 与 SIRT1 的相互作用，并抑制了 SIRT1 介导的 p53 去乙酰化和 p53 诱导的促凋亡基因的反式激活。最终，野生型 PLD2 的过表达而非 LXXLL 突变型 PLD2 的过表达保护细胞免受依托泊苷诱导的细胞凋亡。此外，PLD2 不能防止基因毒性应激下 SIRT1 耗竭诱导的细胞凋亡。总的来说，我们的结果表明 PLD2 是 SIRT1 的正调节因子，并通过 SIRT1 调节 p53 介导的细胞凋亡。