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

doi:10.1073/pnas.0504419102

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

^*Margaret M. Dyson Vision Research Institute, Weill Medical College of Cornell University, New York, NY 10021; ^†Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107; and ^§Jules Stein Eye Institute, ^¶Brain Research Institute, and ^∥Department of Neurobiology, School of Medicine, University of California, Los Angeles, CA 90095

Edited by David D. Sabatini New York University School of Medicine, New York, NY (received for review May 27, 2005)

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, MCT/CD147 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, MCT1/CD147 is polarized to the apical membrane and MCT3/CD147 to the basolateral membrane. The mechanisms responsible for tissue-specific polarized distribution of MCTs are unknown. Here, we demonstrate that CD147 carries sorting information for polarized targeting of the MCT1/CD147 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.

Footnotes

↵ ‡ To whom correspondence may be addressed. E-mail: nancy.philp{at}jefferson.edu or boulan{at}med.cornell.edu.
Author contributions: A.A.D., N.P., and E.R.-B. designed research; A.A.D. and N.P. performed research; J.H. and D.B. contributed new reagents/analytical tools; A.A.D., N.P., and E.R.-B. analyzed data; and A.A.D., N.P., and E.R.-B. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: MDCK, Madin-Darby canine kidney; RPE, retinal pigment epithelium; MCT, monocarboxylate transporter; Endo-H, endoglycosidase-H; LSCM, laser scanning confocal microscopy; siRNA, small interfering RNA; RNAi, RNA interference.