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

mRNA level is controlled by factors that mediate both mRNA synthesis and decay, including the exonuclease Xrn1 - a major mRNA synthesis and decay factor. Here we show that nucleocytoplasmic shuttling of Xrn1 and of some of its associated 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. The decaying RNA binds and masks NLS1, establishing a link between mRNA decay and Xrn1 shuttling. Mutations in the two NLSs, which prevent Xrn1 import, compromise transcription and, unexpectedly, also the cytoplasmic decay of ∼50% of the cellular mRNAs - comparably to Xrn1 deletion. These findings uncover a cytoplasmic mRNA decay pathway that begins in the nucleus. Interestingly, Xrn1 shuttling is required for proper adaptation to environmental changes, in particular to ever changing environmental fluctuations. ### Competing Interest Statement The authors have declared no competing interest.