RNA-controlled nucleocytoplasmic shuttling of mRNA decay factors regulates mRNA synthesis and a novel mRNA decay pathway

mRNA level is controlled by factors that mediate both mRNA synthesis and decay, including the 5’ to 3’ exonuclease Xrn1 - a major mRNA synthesis and decay factor. Here we show that nucleocytoplasmic shuttling of several mRNA decay factors plays a key role in determining both mRNA synthesis and decay. Shuttling is regulated by RNA-controlled binding of the karyopherin Kap120 to two nuclear localization sequences (NLSs) in Xrn1, location of one of which is conserved from yeast to human. The decaying RNA binds and masks NLS1, establishing a link between mRNA decay and Xrn1 shuttling. Preventing Xrn1 import, either by deleting KAP120 or mutating the two Xrn1 NLSs, compromise transcription and, unexpectedly, also the cytoplasmic decay, uncovering a cytoplasmic decay pathway that initiates in the nucleus. Most mRNAs are degraded by both the “classical” and the novel pathways, the ratio between them represents a full spectrum. Importantly, Xrn1 shuttling is required for proper adaptation to environmental changes, in particular to ever changing environmental fluctuations.

信使RNA（mRNA）的水平由同时介导mRNA合成与降解的各类因子所调控，其中包括5'→3'核酸外切酶Xrn1（5' to 3' exonuclease Xrn1）——一类主要的mRNA合成与降解调控因子。本研究证实，多种mRNA降解因子的核质穿梭（nucleocytoplasmic shuttling）在调控mRNA合成与降解过程中均发挥关键作用。该穿梭过程受RNA调控的核转运蛋白Kap120（karyopherin Kap120）与Xrn1上两处核定位序列（NLSs，nuclear localization sequences）的结合所调控，其中一处核定位序列的位置从酵母到人类均保守存在。正在降解的RNA会结合并遮蔽NLS1，从而建立起mRNA降解与Xrn1核质穿梭之间的内在关联。通过敲除KAP120或突变Xrn1的两处NLS来阻断Xrn1的核输入，不仅会损害转录过程，还会意外地影响细胞质中的mRNA降解，这揭示了一条起始于细胞核的细胞质降解通路。大多数mRNA可通过“经典”与“新型”两条通路共同降解，二者的降解比例呈现出完整的分布谱系。尤为重要的是，Xrn1的核质穿梭对于生物体适应环境变化，尤其是持续波动的环境刺激，至关重要。