The identification of barely more than 20,000 human genes was amongst the most surprising outcomes of the human genome project. Alternative splicing provides an essential means of expanding the proteome, enabling a single gene to encode multiple, distinct isoforms by selective inclusion or exclusion of exons from mature mRNA. However, mis-regulation of this process is associated with most human diseases. Here, we examine the impact of post-transcriptional processing on extracellular matrix function, focusing on the complex alternative splicing patterns of tenascin-C, a molecule that can exist in as many as 500 different isoforms. We demonstrate that the pro-inflammatory activity of this endogenous innate immune trigger is controlled by inclusion or exclusion of a novel immunomodulatory site located within domains AD2AD1, identifying this as a mechanism that prevents unnecessary inflammation in healthy tissues but enables rapid immune cell mobilization and activation upon tissue damage, and defining how this goes awry in autoimmune disease.

人类基因组计划最令人惊讶的成果之一是对仅超过 20,000 个人类基因的鉴定。选择性剪接提供了扩展蛋白质组的重要手段，通过选择性地包含或排除成熟 mRNA 的外显子，使单个基因能够编码多个不同的同种型。然而，这个过程的错误调节与大多数人类疾病有关。在这里，我们研究了转录后加工对细胞外基质功能的影响，重点关注生腱蛋白-C 的复杂可变剪接模式，这种分子可以存在于多达 500 种不同的亚型中。我们证明，这种内源性先天免疫触发器的促炎活性是通过包含或排除位于 AD2AD1 域内的新免疫调节位点来控制的，