Tissue-specific SEC31A alternative splicing is regulated by RBM47 and controls lipid transport

The importance of coat protein complex II (COPII) for protein secretion has been known for decades. However, how large cargo like procollagens or chylomicrons are secreted remains incompletely understood, as COPII vesicles are usually too small to accommodate such bulky cargo. Here we introduce alternative splicing as another regulatory layer in controlling secretion of large cargo. We use RNA-seq data from various human tissues to identify tissue-specific alternative splicing in secretion-associated genes. This identifies an uncharacterized exon in SEC31A, a component of the COPII machinery, whose inclusion is highly tissue-specific, with high inclusion, for example, in digestive tissues. We show that inclusion of this exon increases lipid transport, thereby connecting SEC31A alternative splicing with the secretion of large cargo. Furthermore, by correlating SEC31A alternative splicing with the expression of RNA-binding proteins across multiple tissues, we identify and then validate RBM47 as the regulator of SEC31A alternative splicing. This serves as proof-of-principle for a broadly applicable in silico approach to facilitate the identification of <i>trans</i>-acting factors controlling tissue-specific alternative splicing.