Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel.
Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel.
Nat Commun. 2023 Oct 5;14(1):6208. doi: 10.1038/s41467-023-41895-2.
Lysine acetylation has been discovered in thousands of non-histone human proteins, including most metabolic enzymes. Deciphering the functions of acetylation is key to understanding how metabolic cues mediate metabolic enzyme regulation and cellular signaling. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, is acetylated on multiple lysine residues. Using site-specifically acetylated G6PD, we show that acetylation can activate (AcK89) and inhibit (AcK403) G6PD. Acetylation-dependent inactivation is explained by structural studies showing distortion of the dimeric structure and active site of G6PD. We provide evidence for acetylation-dependent K95/97 ubiquitylation of G6PD and Y503 phosphorylation, as well as interaction with p53 and induction of early apoptotic events. Notably, we found that the acetylation of a single lysine residue coordinates diverse acetylation-dependent processes. Our data provide an example of the complex roles of acetylation as a posttranslational modification that orchestrates the regulation of enzymatic activity, posttranslational modifications, and apoptotic signaling.
赖氨酸乙酰化已在数千个人类非组蛋白中被发现，包括大多数代谢酶。破译乙酰化的功能是理解代谢信号如何介导代谢酶调节和细胞信号转导的关键。葡萄糖-6-磷酸脱氢酶（G6PD）是戊糖磷酸途径的限速酶，其多个赖氨酸残基被乙酰化。使用特异性乙酰化的 G6PD，我们表明乙酰化可以激活（AcK89）和抑制（AcK403）G6PD。结构研究表明乙酰化依赖性失活是由于 G6PD 的二聚体结构和活性位点的扭曲。我们提供了证据表明 G6PD 的 K95/97 泛素化和 Y503 磷酸化以及与 p53 的相互作用和早期凋亡事件的诱导依赖于乙酰化。值得注意的是，我们发现单个赖氨酸残基的乙酰化协调了多种依赖于乙酰化的过程。我们的数据提供了一个例子，说明乙酰化作为一种翻译后修饰如何协调酶活性、翻译后修饰和凋亡信号的调节。
