LncRNA-dependent nuclear stress bodies promote intron retention through SR protein phosphorylation

A number of long noncoding RNAs (lncRNAs) are induced in response to specific stresses to construct membrane-less nuclear bodies; however, their function remains poorly understood. Here, we report the role of nuclear stress bodies (nSBs) formed on highly repetitive satellite III (HSATIII) lncRNAs derived from primate-specific satellite III repeats upon thermal stress exposure. A transcriptomic analysis revealed that depletion of HSATIII lncRNAs, resulting in elimination of nSBs, promoted splicing of 533 retained introns during thermal stress recovery. A HSATIII-Comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) analysis identified multiple splicing factors in nSBs, including serine and arginine-rich pre-mRNA splicing factors (SRSFs), the phosphorylation states of which affect splicing patterns. SRSFs are rapidly dephosphorylated upon thermal stress exposure. During stress recovery, CDC like kinase 1 (CLK1) was recruited to nSBs and accelerated the re-phosphorylation of SRSF9, thereby promoting target intron retention. Our findings suggest that HSATIII-dependent nSBs serve as a conditional platform for phosphorylation of SRSFs by CLK1 to promote the rapid adaptation of gene expression through intron retention following thermal stress exposure.

多种长链非编码RNA（long noncoding RNAs, lncRNAs）可响应特定应激刺激被诱导表达，进而组装形成无膜核体，但其具体功能仍有待深入解析。本研究聚焦于热应激暴露后，由灵长类特异性卫星III重复序列衍生的高度重复卫星III（highly repetitive satellite III, HSATIII）长链非编码RNA所组装形成的核应激小体（nuclear stress bodies, nSBs）的功能。转录组分析结果显示，敲除HSATIII长链非编码RNA并消除核应激小体后，可促进热应激恢复期中533个滞留内含子的剪接过程。通过HSATIII相关的基于质谱的RNA结合蛋白综合鉴定（ChIRP-MS）分析，研究团队在核应激小体中鉴定出多种剪接因子，包括富含丝氨酸/精氨酸的前mRNA剪接因子（serine and arginine-rich pre-mRNA splicing factors, SRSFs），其磷酸化状态可调控剪接模式。热应激暴露后，SRSFs会快速发生去磷酸化。在应激恢复阶段，CDC样激酶1（CDC like kinase 1, CLK1）被招募至核应激小体，加速SRSF9的再磷酸化过程，进而促进靶内含子滞留。本研究结果提示，依赖HSATIII的核应激小体可作为条件性平台，通过介导CLK1对SRSFs的磷酸化修饰，促进热应激暴露后通过内含子滞留实现的基因表达快速适应性调控。