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Basolateral sorting signals regulating tissue-specific polarity of heteromeric monocarboxylate transporters in epithelia.
Traffic. 2011 Apr; 12(4):483-98
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25 Feb 2011
DOI: 10.3410/f.8511966.8985067
I found this article very interesting as this is the first detailed study to examine the mechanisms underlying membrane-specific (apical versus basolateral) targeting of heterodimeric monocarboxylate transporters (MCTs) in polarized epithelial cells in a tissue-specific manner. For example, MCT3 and MCT4 of the MCT gene family have always been shown to localize to basolateral membrane domains, but MCT1 has been shown to localize to either the apical or basolateral membrane in different tissues or species. This study provides that missing link to explain this differential membrane sorting behavior of MCT1 versus MCT3/4 and highlights the mechanisms for membrane-specific trafficking of these heterodimeric proteins.
The proton-coupled MCTs are members of the SLC16 gene family of solute transporters and have been shown to play important roles in transport of a variety of monocarboxylates. In this regard, MCT1, MCT3 and MCT4 have been shown to be heterodimeric proteins which form a complex with CD147, a highly glycosylated small transmembrane protein. This complex is assembled in the endoplasmic reticulum and is essential for membrane targeting of these MCTs. Multiple MCTs are often coexpressed in a single epithelium; however, the polarity of the isoforms varies depending on the tissue. For example, it is well accepted that MCT3 and MCT4 localize to basolateral membrane domains in polarized epithelial cells. However, the localization of MCT1 has been shown to differ in different tissues, and has been shown to be different even in the same tissue type but in different species (e.g. in the intestinal epithelium) {1,2}. The sorting signals and mechanisms that regulate the variable localization of MCTs in different epithelia have not been well understood. Early insight into the sorting of MCTs in polarized cells was provided by the author’s identification of a basolateral sorting signal (BLSS) in the cytoplasmic tail of CD147 consisting of a critical leucine residue at 252. The current study, utilizing extensive mutagenesis, truncations, chimeric-fusion-protein approaches and imaging approaches, shows that MCT3 and MCT4 harbor strong and redundant BLSS in their C-terminal cytoplasmic tails that can direct these proteins to the basolateral membrane domains. In contrast, MCT1 lacks a BLSS in its C-terminal cytoplasmic tail and its targeting is dictated by CD147, which contains a weak BLSS that can direct the apical marker Tac, but not p75, to the basolateral membranes. Additional experiments in MDCK cells indicated that basolateral sorting of MCTs was clathrin-dependent but not clathrin-adaptor-AP1B-dependent. These results clearly support the consistently basolateral localization of MCT3 and MCT4 and the variable localization of MCT1 in different epithelia and define a new model for the sorting of heterodimeric transporters in which a hierarchy of apical and basolateral targeting signals within the proteins and/or their accessory subunits regulates their tissue-specific polarity. We believe that this lack of a strong BLSS within the MCT1 (and a weak basolateral signal in CD147) could explain why sometimes MCT1 targets to different plasma membrane domains of the epithelial cells even in the same tissue (e.g. intestine) but in different species depending upon the physiological needs of the epithelial cells. This could explain why MCT1, which has been shown to be important for short-chain fatty acid absorption in the intestine, could preferentially be expressed on either apical or basolateral domains. Future studies to further define the nutritional factors and other mechanisms involved in apical sorting of MCT1 in intestinal epithelial cells would be of interest.
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Dudeja P: F1000Prime Recommendation of [Castorino JJ et al., Traffic 2011, 12(4):483-98]. In F1000Prime, 25 Feb 2011; DOI: 10.3410/f.8511966.8985067. F1000Prime.com/8511966#eval8985067
F1000Prime Recommendations, Dissents and Comments for [Castorino JJ et al., Traffic 2011, 12(4):483-98]. In F1000Prime, 19 Jun 2013; F1000Prime.com/8511966
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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.
© 2011 John Wiley & Sons A/S.
DOI: 10.1111/j.1600-0854.2010.01155.x
PMID: 21199217
