A novel splicing regulator shares a nuclear import pathway with SR proteins

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Abstract
Alternative splicing of precursor mRNA is often regulated by serine/arginine‐rich proteins (SR proteins) and hnRNPs, and varying their concentration in the nucleus can be a mechanism for controlling splice site selection. To understand the nucleocytoplasmic transport mechanism of splicing regulators is of key importance. SR proteins are delivered to the nucleus by transportin‐SRs (TRN‐SRs), importin β‐like nuclear transporters. Here we identify and characterize a non‐SR protein, RNA‐binding motif protein 4 (RBM4), as a novel substrate of TRN‐SR2. TRN‐SR2 interacts specifically with RBM4 in a Ran‐sensitive manner. TRN‐SR2 indeed mediates the nuclear import of a recombinant protein containing the RBM4 C‐terminal domain. This domain serves as a signal for both nuclear import and export, and for nuclear speckle targeting. Finally, both in vivo and in vitro splicing analyses demonstrate that RBM4 not only modulates alternative pre‐mRNA splicing but also acts antagonistically to authentic SR proteins in splice site and exon selection. Thus, a novel splicing regulator with opposite activities to SR proteins shares an identical import pathway with SR proteins to the nucleus.