ATP-citrate lyase (ACLY) links carbohydrate and lipid metabolism and provides nucleocytosolic acetyl-CoA for protein acetylation. has two major splice isoforms: the full-length canonical “long” isoform and an uncharacterized “short” isoform in which exon 14 is spliced out. Exon 14 encodes 10 amino acids within an intrinsically disordered region and includes at least one dynamically phosphorylated residue. Both isoforms are expressed in healthy tissues to varying degrees. Analysis of human transcriptomic data revealed that the percent spliced in (PSI) of exon 14 is increased in several cancers and correlated with poorer overall survival in a pan-cancer analysis, though not in individual tumor types. This prompted us to explore potential biochemical and functional differences between ACLY isoforms. Here, we show that there are no discernible differences in enzymatic activity or stability between isoforms or phosphomutants of ACLY . Similarly, both isoforms and phosphomutants were able to rescue ACLY functions, including fatty acid synthesis and bulk histone acetylation, when re-expressed in knockout cells. Deletion of exon 14 in mice did not overtly impact development or metabolic physiology nor did it attenuate tumor burden in a genetic model of intestinal cancer. Notably, expression of epithelial splicing regulatory protein 1 () is highly correlated with PSI. We report that splicing is regulated by . In turn, both expression and PSI are correlated with specific immune signatures in tumors. Despite these intriguing patterns of splicing in healthy and cancer tissues, functional differences between the isoforms remain elusive.

中文翻译：

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ACLY 选择性剪接与癌症表型相关


ATP-柠檬酸裂解酶 (ACLY) 连接碳水化合物和脂质代谢，并为蛋白质乙酰化提供核胞质乙酰辅酶 A。有两种主要的剪接亚型：全长规范的“长”亚型和未表征的“短”亚型，其中外显子 14 被剪接。外显子 14 编码本质上无序区域内的 10 个氨基酸，并包含至少一个动态磷酸化残基。两种同工型在健康组织中都有不同程度的表达。对人类转录组数据的分析显示，在多种癌症中，外显子 14 的剪接百分比 (PSI) 有所增加，并且在泛癌分析中与较差的总体生存率相关，但在个别肿瘤类型中并非如此。这促使我们探索 ACLY 亚型之间潜在的生化和功能差异。在这里，我们表明 ACLY 的异构体或磷酸突变体之间的酶活性或稳定性没有明显差异。同样，当在敲除细胞中重新表达时，同工型和磷酸突变体都能够挽救 ACLY 功能，包括脂肪酸合成和大量组蛋白乙酰化。小鼠中外显子 14 的缺失并没有明显影响发育或代谢生理学，也没有减轻肠癌遗传模型中的肿瘤负担。值得注意的是，上皮剪接调节蛋白 1 () 的表达与 PSI 高度相关。我们报告拼接受 .反过来，表达和 PSI 都与肿瘤中的特异性免疫特征相关。尽管健康组织和癌症组织中存在这些有趣的剪接模式，但亚型之间的功能差异仍然难以捉摸。