Basolateral Sorting Signals Regulating Tissue‐Specific Polarity of Heteromeric Monocarboxylate Transporters in Epithelia

Abstract

Many solute transporters are heterodimers comprised 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 basolateral sorting signals in the catalytic and/or accessory subunits regulates their tissue-specific polarity.

Lactate-H+Transport Is a Significant Component of the In Vivo Corneal Endothelial Pump

“…24 MCT4 has a basolateral sorting signal in the C-terminal portion of the cytoplasmic tail. 31 Nevertheless, some studies show that MCT4 can localize to the apical membranes in certain tissues. 32,33 Even in the same organ (e.g., small and large intestine), the expression profile of MCT4 varies depending on the region.…”

The Na+-K+-ATPase as self-adhesion molecule and hormone receptor

“…Finally, Na ϩ -K ϩ -ATPase and VSV-G travel in separate post-Golgi transport intermediates, demonstrating directly that multiple routes exist for transport from the Golgi to the basolateral membrane in polarized epithelial cells (43). Plasma membrane proteins composed of two or more subunits, such as Na-K-ATPase and monocarboxylate transporters, are challenging to study in terms of sorting mechanisms as sorting signals may be present in one or more subunits which act hierarchically and can be recognized by different components of the cellular sorting machinery (18,89).…”

Polarized sorting and trafficking in epithelial cells

“…In polarized epithelial cells, only recent functional experiments provided the evidence that clathrin is required for basolateral plasma-membrane protein sorting [145,146]. Knockdown of the clathrin heavy chain in MDCK cells depolarized most basolateral proteins, by interfering with their biosynthetic delivery and recycling, but did not affect the polarity of apical proteins.…”