Inhibition of the cellular secretion of cholesteryl ester transfer protein by a variant protein formed by alternative splicing of mRNA.

Alternative splicing of mRNA is often used as a regulatory switch, determining whether a functional protein is made or not. The plasma cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from high density lipoproteins to other lipoproteins. In addition to the mRNA encoding plasma CETP, human tissues contain an alternatively spliced variant in which exon 9-derived sequences are omitted. To determine a possible regulatory role of alternative splicing, COS cells were co-transfected with full-length and exon 9-deleted cDNAs. The exon 9-deleted protein was poorly secreted and inhibited the secretion of full-length CETP, due to formation of an intracellular heteromeric complex between full-length and exon 9-deleted proteins. The findings suggest a novel use of alternative splicing to generate a poorly secreted protein variant, which complexes with the active form and prevents its secretion by cells.