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J. Biol. Chem., Vol. 281, Issue 45, 34601-34609, November 10, 2006

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Acylation of CD44 and Its Association with Lipid Rafts Are Required for Receptor and Hyaluronan Endocytosis^*

From the Department of Biochemistry, Rush Medical College, Rush University Medical Center, Chicago, Illinois 60612

CD44 is a cell surface receptor for the extracellular matrix macromolecule hyaluronan. In addition, CD44 mediates the endocytosis of hyaluronan leading to its subsequent degradation within lysosomes. Using model systems of COS-7 and Flp-293 cells, we demonstrate that the association of CD44 with lipid rafts is essential for the endocytosis of hyaluronan but not the extracellular binding. Further, we demonstrate that palmitoylation of CD44 on two highly conserved cysteine residues is essential for the association with lipid rafts as determined by density gradient ultracentrifugation. Mutations of either cysteine residues or pretreatment of cells with the palmitic acid analog 2-bromopalmitate, reduced the [³H]palmitic acid incorporation into CD44 and prevented CD44-lipid rafts association. Preventing CD44 palmitoylation had no effect on the binding of hyaluronan but inhibited hyaluronan internalization. The turnover of the CD44 receptor itself was also affected by blocking its association with lipid rafts. Using cycloheximide to prevent de novo protein synthesis, palmitoylation-deficient cysteine mutants underwent slower turnover from cell surface compared with the palmitoylation-intact wild type, as determined by immunofluorescence and Western blotting. These results indicate that palmitoylation of CD44 is a critical driving determinant to CD44 association with lipid rafts and, concomitantly, the rates of hyaluronan endocytosis and CD44 turnover from cell surface.

Received for publication, February 16, 2006 , and in revised form, July 6, 2006.

^* This work was supported in part by National Institutes of Health Grants RO1-AR43384 and P50-AR39239. This work was submitted as partial fulfillment of a Ph.D. degree (for S. P. T.), from the Dept. of Biochemistry, Graduate College of Rush University, Chicago, IL. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, Rush Medical College Rush University Medical Center, 1735 West Harrison St., Chicago, IL 60612. Tel.: 312-942-7837; Fax: 312-942-3053; E-mail: Warren_Knudson{at}rush.edu.

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