BSB PhD Exit Seminar: Characterising the regulatory effects of splice variants of transporters

Abstract

Membrane transport proteins, also known as transporters, are crucial for the maintenance of cell physiology by facilitating the movement of ions, nutrients, metabolites, and waste across cell membranes. Transporter function can be expanded through the mechanism of alternative splicing, which can produce distinct protein isoforms from a single gene. A review of the literature has uncovered a subset of naturally occurring splice variants of eukaryotic transporters with striking similarities. The transporters are unrelated and from a wide range of organisms (for instance, the malaria parasite, the honeybee, and humans); yet their splice variants are all predicted to have grossly deformed topologies, are unable to transport the substrate(s) of their full-length transporter, and instead downregulate the expression of their full-length protein. During my PhD, I utilised the Xenopus laevis oocyte expression system to characterise the regulatory activities of a selection of these transporter splice variants. My results highlighted that despite the diversity in the transporters studied, their splice variants exerted similar regulatory effects on their full-length protein. Importantly, I found that the transporter splice variants also downregulated the expression of unrelated transporters. These findings suggested that the splice variants may act through a regulatory mechanism that is conserved in eukaryotes. To gain insight into the nature of this potential mechanism, I investigated a number of possible modes-of-action of the transporter splice variants in X. laevis oocytes. This work contributes to our understanding of this subset of seemingly ‘non-functional’ splice variants of transporters that may mediate a conserved regulatory mechanism.