Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin 130024, People's Republic Of China.
Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, People's Republic Of China.
Proc Natl Acad Sci U S A. 2024 Oct 15;121(42):e2402674121. doi: 10.1073/pnas.2402674121. Epub 2024 Oct 10.
Elevated lipid synthesis is one of the best-characterized metabolic alterations in cancer and crucial for membrane expansion. As a key rate-limiting enzyme in de novo fatty acid synthesis, ATP-citrate lyase (ACLY) is frequently up-regulated in tumors and regulated by posttranslational modifications (PTMs). Despite emerging evidence showing -GlcNAcylation on ACLY, its biological function still remains unknown. Here, we observed a significant upregulation of ACLY -GlcNAcylation in various types of human tumor cells and tissues and identified S979 as a major -GlcNAcylation site. Importantly, S979 -GlcNAcylation is required for substrate CoA binding and crucial for ACLY enzymatic activity. Moreover, it is sensitive to glucose fluctuation and decisive for fatty acid synthesis as well as tumor cell proliferation. In response to EGF stimulation, both S979 -GlcNAcylation and previously characterized S455 phosphorylation played indispensable role in the regulation of ACLY activity and cell proliferation; however, they functioned independently from each other. In vivo, streptozocin treatment- and EGFR overexpression-induced growth of xenograft tumors was mitigated once S979 was mutated. Collectively, this work helps comprehend how cells interrogate the nutrient enrichment for proliferation and suggests that although mammalian cell proliferation is controlled by mitogen signaling, the ancient nutrition-sensing mechanism is conserved and still efficacious in the cells of multicellular organisms.
脂质合成升高是癌症中最典型的代谢改变之一，对膜扩张至关重要。作为从头合成脂肪酸的关键限速酶，ATP-柠檬酸裂解酶（ACLY）在肿瘤中经常上调，并受翻译后修饰（PTMs）调节。尽管有证据表明 ACLY 存在 -GlcNAc 化，但它的生物学功能仍然未知。在这里，我们观察到各种类型的人肿瘤细胞和组织中 ACLY 的 -GlcNAc 化显著上调，并确定 S979 为主要的 -GlcNAc 化位点。重要的是，S979 的 -GlcNAc 化对于底物 CoA 的结合是必需的，并且对于 ACLY 的酶活性至关重要。此外，它对葡萄糖波动敏感，对脂肪酸合成和肿瘤细胞增殖也至关重要。在 EGF 刺激下，S979 的 -GlcNAc 化和之前表征的 S455 磷酸化都在 ACLY 活性和细胞增殖的调节中发挥了不可或缺的作用；然而，它们彼此独立地发挥作用。在体内，一旦 S979 发生突变，链脲佐菌素处理和 EGFR 过表达诱导的异种移植肿瘤生长就会减轻。总的来说，这项工作有助于理解细胞如何检测增殖所需的营养丰富程度，并表明尽管哺乳动物细胞的增殖受有丝分裂信号的控制，但古老的营养感应机制在多细胞生物的细胞中仍然保守且有效。
