The early RNA decay factor ZC3H18 directs first intron splicing.

Pre-mRNA splicing is essential for gene expression. In human cells, the cap-binding complex (CBC) has long been known to facilitate first intron splicing, but it is by an unknown mechanism. The CBC also promotes early RNA decay by recruiting the nuclear exosome targeting (NEXT) complex via the linker proteins ARS2 and ZC3H18. How the CBC orchestrates these opposite activities is elusive. Here, we show that ZC3H18 interacts with three splicing factors, PRPF40A, PRP4K, and FNBP4, to stimulate first intron splicing genome wide. Linking this unexpected function of ZC3H18 to the CBC, disruption of the CBC-ARS2-ZC3H18 axis corrupts first intron splicing. Although ZC3H18 acts in both RNA decay and splicing, its association with splicing factors is mutually exclusive with its binding to NEXT. Our results rationalize cap-stimulated first intron splicing mechanistically and suggest that splicing factors displace NEXT from ZC3H18, designating the nascent RNA to a productive pathway at the expense of RNA decay.