PDF(Pubmed)
Abstract：
Interleukin-1α is a suggested dual-function cytokine that diverged from interleukin-1β in mammals potentially by acquiring additional biological roles that relate to highly conserved regions in the pro-domain of interleukin-1α, including a nuclear localisation sequence and histone acetyltransferase-binding domains. Why evolution modified pro-interleukin-1α\'s subcellular location and protein interactome, and how this shaped interleukin-1α\'s intracellular role, is unknown. Here we show that TurboID proximity labelling with pro-interleukin-1α suggests a nuclear role for pro-interleukin-1α that involves interaction with histone acetyltransferases, including EP300. We also identify and validate inactivating mutations in the pro-interleukin-1α nuclear localisation sequence of multiple mammalian species, including toothed whales, castorimorpha and marsupials. However, histone acetyltransferase-binding domains are conserved in those species that have lost pro-interleukin-1α nuclear localisation. Together, these data suggest that histone acetyltransferase binding and nuclear localisation occurred together, and that while some species lost the nuclear localisation sequence in their pro-interleukin-1α, histone acetyltransferase binding ability was maintained. The nuclear localisation sequence was lost from several distinct species at different evolutionary times, suggesting convergent evolution, and that the loss of the nuclear localisation sequence confers some important biological outcome.
摘要：
白细胞介素-1α是一种双重功能细胞因子，可能通过获得与白细胞介素-1α前结构域中高度保守区域相关的其他生物学作用，在哺乳动物中与白细胞介素-1β分离。包括核定位序列和组蛋白乙酰转移酶结合域。为什么进化改变了白细胞介素-1α的亚细胞定位和蛋白质相互作用组，以及如何塑造白细胞介素-1α的细胞内作用，是未知的。在这里，我们表明，TurboID与前白介素-1α的邻近标记表明前白介素-1α的核作用，涉及与组蛋白乙酰转移酶的相互作用，包括EP300。我们还鉴定并验证了多种哺乳动物物种的前白介素-1α核定位序列中的失活突变，包括齿鲸,蓖麻和有袋动物。然而,组蛋白乙酰转移酶结合域在那些丢失了前白细胞介素-1α核定位的物种中是保守的。一起,这些数据表明组蛋白乙酰转移酶结合和核定位同时发生，虽然有些物种失去了白细胞介素-1α前体的核定位序列，保持了组蛋白乙酰转移酶的结合能力。核定位序列在不同的进化时间从几个不同的物种中丢失，表明趋同进化，核定位序列的丢失赋予了一些重要的生物学结果。
