cules that first emerge from the transcription of a gene. These pre-mRNAs contain sequences (exons) encoding information required to make a protein, interspersed with non-coding regions (introns) that must typically be removed before protein production can start. A large molecular machine, the spliceosome, distinguishes introns from exons, removes the former and joins the latter to create a mature mRNA template.
基因调控中一个关键但常被忽视的环节是前体信使RNA的加工过程——这是基因转录后最先生成的分子。这些前体mRNA包含编码蛋白质信息的外显子序列，其间穿插着需要在蛋白质合成前去除的非编码区域（内含子）。剪接体这一大型分子机器能够识别内外显子边界，去除内含子并连接外显子形成成熟的mRNA模板。
Cells can fine-tune these complex splicing events to control what proteins are made, when, and in what form (Boutz et al., 2015). Thus, splicing allows the organism to meet changing demands quickly and flexibly. Deliberately leaving in “detained introns” prevents target pre-mRNAs from being exported from the nucleus, which allows the cell to delay or prevent the production of certain proteins without degrading the associated RNA transcripts (Yap et al., 2012). Exon skipping, on the other hand, occurs when the spliceosome skips an exon to allow an mRNA to be produced albeit with an altered coding sequence. “Decoy” exons also occur. Although their mode of action remains unclear, these exons contained within introns are believed to recruit and then “stall” the spliceosome, preventing it from proceeding with the normal splicing process.
细胞可通过精细调控这些复杂的剪接事件来决定蛋白质
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的合成时序与形式（Boutz等，2015）。这种机制使生物能快速灵活地应对变化需求。刻意保留的”滞留内含子”可阻止靶向pre-mRNA输出细胞核，使细胞能在不降解RNA转录本的情况下延迟或抑制特定蛋白质生成（Yap等，2012）。当剪接体跳过外显子时会发生外显子跳跃，虽产生mRNA但其编码序列已改变。还存在”诱饵外显子”现象——尽管作用机制尚不明确，这类内含子中的外显子被认为能招募并”阻滞”剪接体，干扰正常剪接进程。
Recent work has shown that a highly dynamic protein modification, known as O-GlcNAc, plays a key role in regulating detained intron splicing (Tan et al., 2020). O-GlcNAcylation consists of the addition of a small sugar molecule (GlcNAc) onto certain amino acids, which can alter the activity and location of thousands of proteins in a cell. It helps modulate gene expression and many crucial signaling pathways, such as those involved in responding to DNA damage or maintaining cell identity in early development (Bond and Hanover, 2015; Zachara et al., 2022; Fehl and Hanover, 2022). O-GlcNAc levels vary in response to broader environmental signals, in particular stressors or variations in nutrient availability. As such, this process allows cells to adjust their response and retain their internal balance in the face of ever-changing conditions. Finely regulating O-GlcNAcylation is therefore crucial for survival, with deregulation being linked to some forms of X-linked intellectual disability (Konzman et al., 2020; Vaidyanathan et al., 2017).
最新研究显示，一种高度动态的蛋白质翻译后修饰——O-GlcNAc修饰在调控内含子滞留中起关键作用（Tan等，2020）。O-GlcNAc糖基化修饰是指将N-乙酰葡萄糖胺（GlcNAc）添加至特定氨基酸的修饰过程，这种修饰能改变细胞中数千种蛋白质的活性与定位。它参与调控基因表达和多个关键信号通路，如DNA损伤应答、早期发育中细胞身份维持等（Bond与Hanover，2015；Zachara等，2022；Fehl与Hanover，2022）。O-GlcNAc水平会随环境信号（特别是应激源或营养物质变化）动态调整，使细胞在不断变化的环境中维持内稳态。精准调控O-GlcNAc修饰对生存至关重要，其失调与某些X染色体连锁智力障碍疾病相关（Konzman等，2020；Vaidyanathan等，2017）。
Interestingly, the control of O-GlcNAcylation itself seems to be linked to detained intron splicing (Tan et al., 2020). Two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively add and remove GlcNAc to/from proteins (Bond and Hanover, 2015; Zachara et al., 2022). An intricate feedback loop maintains stability in the system: when O-GlcNAc levels rise, for instance, OGT production decreases while that of OGA increases. More precisely, under high O-GlcNAc levels, introns are retained in the pre-mRNA transcript of the OGT gene, preventing protein expression. A similar mechanism unfolds for OGA when O-GlcNAc is low (Figure 1A and B; Park et al., 2017; Tan et al., 2020). Should this fail to restore healthy levels of O-GlcNAc, the cell responds by specifically changing detained intron splicing across the whole genome. What controls this O-GlcNAc-driven splicing regulation, however, is still poorly understood. Now, in eLife, Ashwin Govindan and Nicholas Conrad from the University of Texas Southwestern Medical Center report having identified the splicing factor SFSWAP as a key player required for this process (Figure 1C; Govindan and Conrad, 2025).
有趣的是，O-GlcNAc修饰本身的调控也与内含子滞留存在关联（Tan等，2020）。O-GlcNAc转移酶（OGT）和O-GlcNAc酶（OGA）分别负责将GlcNAc添加到蛋白上或将其去除（Bond与Hanover，2015；Zachara等，2022）。该系统通过精巧的反馈环维持稳定：例如当O-GlcNAc水平升高时，OGT生成减少而OGA增加。更精确地说，高O-GlcNAc水平下，OGT基因pre-mRNA会保留内含子从而抑制蛋白表达；当O-GlcNAc水平低时，OGA基因呈现类似机制（图1A和B；Park等，2017；Tan等，2020）。当这种机制无法恢复O-GlcNAc的健康水平时，细胞会通过改变全基因组范围的内含子滞留作出响应。但这种O-GlcNAc驱动的剪接调控机制尚不清楚。德州大学西南医学中心的Ashwin Govindan和Nicholas Conrad在eLife发表的研究中鉴定出剪接因子SFSWAP是该过程的关键调控者（图1C；Govindan与Conrad，2025）。
