title: Basolateral sorting signals regulating tissue-specific polarity of heteromeric monocarboxylate transporters in epithelia.
abstract: Many solute transporters are heterodimers composed of non-glycosylated catalytic and glycosylated accessory subunits. These transporters are specifically polarized to the apical or basolateral membranes of epithelia, but this polarity may vary to fulfill tissue-specific functions. To date, the mechanisms regulating the tissue-specific polarity of heteromeric transporters remain largely unknown. Here, we investigated the sorting signals that determine the polarity of three members of the proton-coupled monocarboxylate transporter (MCT) family, MCT1, MCT3 and MCT4, and their accessory subunit CD147. We show that MCT3 and MCT4 harbor strong redundant basolateral sorting signals (BLSS) in their C-terminal cytoplasmic tails that can direct fusion proteins with the apical marker p75 to the basolateral membrane. In contrast, MCT1 lacks a BLSS and its polarity is dictated by CD147, which contains a weak BLSS that can direct Tac, but not p75 to the basolateral membrane. Knockdown experiments in MDCK cells indicated that basolateral sorting of MCTs was clathrin-dependent but clathrin adaptor AP1B-independent. Our results explain the consistently basolateral localization of MCT3 and MCT4 and the variable localization of MCT1 in different epithelia. They introduce a new paradigm for the sorting of heterodimeric transporters in which a hierarchy of apical and BLSS in the catalytic and/or accessory subunits regulates their tissue-specific polarity.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Castorino
authors.forename: Sylvie
authors.initials: S
authors.lastname: Deborde
authors.forename: Ami
authors.initials: A
authors.lastname: Deora
authors.forename: Ryan
authors.initials: R
authors.lastname: Schreiner
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Gallagher-Colombo
authors.forename: Enrique
authors.initials: E
authors.lastname: Rodriguez-Boulan
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Philp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051926:Basigin / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity / Q000502:physiology*; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D008561:Membrane Fusion / Q000502:physiology; D050576:Membrane Fusion Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D027501:Monocarboxylic Acid Transporters / Q000737:chemistry / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology*
chemical_list: D002966:Clathrin; D050576:Membrane Fusion Proteins; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D021382:Protein Sorting Signals; D051926:Basigin