Mechanisms regulating tissue-specific polarity of monocarboxylate transporters and their chaperone CD147 in kidney and retinal epithelia

Abstract

Proton-coupled monocarboxylate transporters (MCT) MCT1, MCT3, and MCT4 form heterodimeric complexes with the cell surface glycoprotein CD147 and exhibit tissue-specific polarized distributions that are essential for maintaining lactate and pH homeostasis. In the parenchymal epithelia of kidney, thyroid, and liver, MCT͞CD147 heterocomplexes are localized in the basolateral membrane where they transport lactate out of or into the cell depending on metabolic conditions. A unique distribution of lactate transporters is found in the retinal pigment epithelium (RPE), which regulates lactate levels of the outer retina. In RPE, MCT1͞ CD147 is polarized to the apical membrane and MCT3͞CD147 to the basolateral membrane. The mechanisms responsible for tissuespecific polarized distribution of MCTs are unknown. Here, we demonstrate that CD147 carries sorting information for polarized targeting of the MCT1͞CD147 hetero-complexes in kidney and RPE cells. In contrast, MCT3 and MCT4 harbor dominant sorting information that cotargets CD147 to the basolateral membrane in both epithelia. RNA interference experiments show that MCT1 promotes CD147 maturation. Our results open a unique paradigm to study the molecular basis of tissue-specific polarity.apical ͉ basolateral ͉ polarized epithelium

Basigin/CD147 Promotes Renal Fibrosis after Unilateral Ureteral Obstruction

“…Bsg expression was detected on the basolateral side of the proximal and distal tubules in Bsg ϩ/ϩ mice before UUO operation ( Figure 4A), consistent with a previous report. 48 UUO operation transiently and slightly enhanced Bsg expression, reaching the maximum level at day 1 ( Figure 4A). However, Bsg expression decreased thereafter, and became very low at day 14 ( Figure 4A).…”

EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis

“…Finally, EMMPRIN has been suggested to interact with a wide variety of molecules at the cell surface, such as cyclophilins, integrins, caveolin-1, monocarboxylate transporters (Berditchevski et al, 1997;Sun and Hemler, 2001;Deora et al, 2005;Yurchenko et al, 2005) and even an ability to oligomerize and dimerize in both a cis and trans manner (Fadool and Linser, 1996;Yu et al, 2008). Determining which, if any, of these interactions are important for EMMPRIN's role in tumorigenesis warrants further investigation and is the basis of our current research.…”

Lactate Transport and Signaling in the Brain: Potential Therapeutic Targets and Roles in Body—Brain Interaction

“…Sorting signals in the C-terminal tail direct MCT3 and MCT4 to the basolateral membrane of retinal pigment epithelium cells, whereas MCT1, which lacks such basolateral sorting signal, 20 requires interaction with basigin for targeting to the apical membrane. 21 The MCT isoforms have different affinities for lactate and other substrates, partly correlating with their tissue distributions: highaffinity isoforms (MCT1 and MCT2) are expressed in cells that mainly import lactate, the low-affinity isoform (MCT4) in lactateexporting cells. Consistent with this, MCT4 has a very low affinity for pyruvate, which saves pyruvate for conversion to lactate by lactate dehydrogenase concomitantly converting NADH into NAD + , which serves to maintain glycolysis.…”