Basolateral sorting signals regulating tissue-specific polarity of heteromeric monocarboxylate transporters in epithelia

Traffic. 2011 Apr;12(4):483-98. doi: 10.1111/j.1600-0854.2010.01155.x. Epub 2011 Feb 1.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Basigin / metabolism
  • Cell Membrane / metabolism
  • Cell Polarity / physiology*
  • Cells, Cultured
  • Clathrin / metabolism
  • Epithelium / metabolism*
  • Gene Knockdown Techniques
  • Membrane Fusion / physiology
  • Membrane Fusion Proteins / metabolism
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Monocarboxylic Acid Transporters / chemistry
  • Monocarboxylic Acid Transporters / metabolism*
  • Protein Sorting Signals / physiology*
  • Protein Transport / physiology*

Substances

  • Clathrin
  • Membrane Fusion Proteins
  • Membrane Transport Proteins
  • Monocarboxylic Acid Transporters
  • Protein Sorting Signals
  • Basigin