Key result
Cathepsin B mRNA constructs missing exons 2 and 3 were biosynthetically more efficient than full-length counterparts, and a truncated chimeric product induced cell death in mammalian cells.
Alternative splicing of cathepsin B pre-mRNA, specifically the loss of exons 2 and 3, increases its biosynthetic rate, which may contribute to pathologies characterized by abnormal connective tissue breakdown.
Truncated cathepsin B variants may drive tissue pathology; hypothesis-generating for splicing-targeted therapies in connective tissue disorders.
The cysteine peptidase cathepsin B is responsible for connective tissue breakdown in several diseases. The pathological expression of cathepsin B may depend on the structure of its mRNA. We investigated the translational efficiency of the cathepsin B mRNA untranslated regions (UTRs) using fusion constructs to green fluorescent protein (GFP) and luciferase. Transfection of fusion constructs with GFP and luciferase containing the full-length 5'-UTR, the variant lacking exon 2, and that lacking exons 2 and 3 into mammalian cells, resulted in modulation of the biosynthetic rate of cathepsin B in a cell-specific manner. Constructs missing these exons were biosynthetically more efficient than the full-length counterpart. Luciferase was cloned upstream of the 3'-UTR, downstream of the 5'-UTR, or sandwiched between the 5'- and the 3'-UTR. The UTRs of cathepsin B downregulated luciferase biosynthesis moderately when present individually, with the 3'-UTR being more efficient than the 5'-UTR, and downregulated it even more when present simultaneously. A truncated cathepsin B-GFP chimeric product derived from the 5'-UTR missing exons 2 and 3 induced cell death. The increased biosynthetic rate and abnormal trafficking of cathepsin B observed in pathologies such as cancer and osteoarthritis may depend on alternative splicing of pre-mRNA.
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Zwicky et al. (2003) studied this question. Cathepsin B mRNA UTR fusion constructs vs. Full-length constructs was evaluated on Translational efficiency and biosynthetic rate. Cathepsin B mRNA constructs missing exons 2 and 3 were biosynthetically more efficient than full-length counterparts, and a truncated chimeric product induced cell death in mammalian cells.
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