RNA splicing is pivotal in post-transcriptional gene regulation, yet the exponential expansion of intron length in humans poses a challenge for accurate splicing. Here, we identify hnRNPM as an essential RNA-binding protein that suppresses cryptic splicing through binding to deep introns, maintaining human transcriptome integrity. Long interspersed nuclear elements (LINEs) in introns harbor numerous pseudo splice sites. hnRNPM preferentially binds at intronic LINEs to repress pseudo splice site usage for cryptic splicing. Remarkably, cryptic exons can generate long dsRNAs through base-pairing of inverted ALU transposable elements interspersed among LINEs and consequently trigger an interferon response, a well-known antiviral defense mechanism. Significantly, hnRNPM-deficient tumors show upregulated interferon-associated pathways and elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity by repressing cryptic splicing and suggest that targeting hnRNPM in tumors may be used to trigger an inflammatory immune response, thereby boosting cancer surveillance.

RNA 剪接在转录后基因调控中至关重要，但人类内含子长度的指数增长对精确剪接提出了挑战。在这里，我们将 hnRNPM 确定为一种重要的 RNA 结合蛋白，它通过与深层内含子结合来抑制隐性剪接，从而维持人类转录组的完整性。内含子中的长散布核元件（LINE）包含许多假剪接位点。 hnRNPM 优先在内含子 LINE 处结合，以抑制隐秘剪接的伪剪接位点使用。值得注意的是，神秘的外显子可以通过散布在 LINE 中的反向 ALU 转座元件的碱基配对生成长 dsRNA，从而触发干扰素反应，这是一种众所周知的抗病毒防御机制。值得注意的是，hnRNPM 缺陷的肿瘤表现出干扰素相关通路上调和免疫细胞浸润升高。这些发现揭示了 hnRNPM 通过抑制隐秘剪接而成为转录组完整性的守护者，并表明靶向肿瘤中的 hnRNPM 可用于触发炎症免疫反应，从而增强癌症监测。