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N. J. Philp, J. J. Castorino, E. J. Rodriguez-Boulan; The COOH-Terminal Tails of Mct3 and Mct4 Contain Novel Motifs That Target the Heteromeric Transport to the Basolateral Membrane. Invest. Ophthalmol. Vis. Sci. 2010;51(13):466.
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Epithelial cells depend on the polarized distribution of metabolic transporters for vectorial transport of ions, fluid and metabolites into and out of tissue compartments to maintain metabolic homeostasis. The transport of lactate into and out of cells is facilitated by proton-coupled monocarboxylate transporters (MCT) 1, 3, and 4, which are expressed as heteromeric complexes comprised of a catalytic subunit (MCT) and an accessory subunit, CD147. Trafficking of MCT-CD147 heterocomplexes in epithelial cells presents a novel sorting paradigm because MCT-CD147 complexes are found in both apical and basolateral membranes depending on the epithelium. The basolateral sorting sequence of CD147 was identified as a single leucine residue in the C-terminal cytoplasmic tail. In the present studies, we identified the basolateral sorting sequences of MCT3 and MCT4.
Co-expression of MCT3 and MCT4 truncation mutants in cells stably expressing CD147-L252A provided us with a model system to identify the general location of their basolateral sorting sequences (BLSS). p75-MCT chimeric constructs transfected into MDCK cells were used to identify specific residues required for basolateral sorting. Polarity of all constructs was assessed using confocal immunofluorescence microscopy.
BLSS were found within the C-terminal cytoplasmic tails of MCT3 and MCT4, while the C-terminal tail of MCT1 did not harbor basolateral sorting activity. Two BLSS were present in the C-terminal tail of MCT3 which both contained acidic clusters. A single bipartite sorting sequence comprised of an upstream acidic cluster and a down stream di-proline was identified in the C-terminal tail of MCT4.
Trafficking of most heteromeric transporters to the plasma membrane is regulated by the catalytic subunit. In contrast, we have shown that trafficking of MCT/CD147 lactate transporters to the plasma membrane can be regulated by either the catalytic subunit or the accessory subunit depending on the MCT isoform. Our studies pave the way to a molecular understanding of the trafficking of heteromeric solute transporters.
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