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CD82 endocytosis and cholesterol-dependent reorganization of tetraspanin webs and lipid rafts

Congfeng Xu^*,,,,1, Yanhui H. Zhang^*,,,,1, Muthusamy Thangavel^||, Mekel M. Richardson^*,,,, Li Liu^*,,,, Bin Zhou^*,,,, Yi Zheng^¶, Rennolds S. Ostrom^|| and Xin A. Zhang^*,,,,2

^* Vascular Biology Center,

Cancer Center,

Department of Medicine,

Department of Molecular Science, and

^|| Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and

^¶ Division of Experimental Hematology, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA

² Correspondence: Vascular Biology Center, Coleman Bldg. Room H300, 956 Court Ave., Memphis, TN 38163, USA. E-mail: xazhang{at}utmem.edu

Tetraspanin CD82 suppresses cell migration, tumor invasion, and tumor metastasis. To determine the mechanism by which CD82 inhibits motility, most studies have focused on the cell surface CD82, which forms tetraspanin-enriched microdomains (TEMs) with other transmembrane proteins, such as integrins. In this study, we found that CD82 undergoes endocytosis and traffics to endosomes and lysosomes. To determine the endocytic mechanism of CD82, we demonstrated that dynamin and clathrin are not essential for CD82 internalization. Depletion or sequestration of sterol in the plasma membrane markedly inhibited the endocytosis of CD82. Despite the demand on Cdc42 activity, CD82 endocytosis is distinct from macropinocytosis and the documented dynamin-independent pinocytosis. As a TEM component, CD82 reorganizes TEMs and lipid rafts by redistributing cholesterol into these membrane microdomains. CD82-containing TEMs are characterized by the cholesterol-containing microdomains in the extreme light- and intermediate-density fractions. Moreover, the endocytosis of CD82 appears to alleviate CD82-mediated inhibition of cell migration. Taken together, our studies demonstrate that lipid-dependent endocytosis drives CD82 trafficking to late endosomes and lysosomes, and CD82 reorganizes TEMs and lipid rafts through redistribution of cholesterol.—Xu, C., Zhang, Y. H., Thangavel, M., Richardson, M. M., Liu, L., Zhou, B., Zheng, Y., Ostrom, R. S., Zhang, X. A. CD82 endocytosis and cholesterol-dependent reorganization of tetraspanin webs and lipid rafts.

Key Words: cell migration • membrane microdomain • protein trafficking • sterol lipid