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J. Biol. Chem., Vol. 281, Issue 34, 24803-24817, August 25, 2006

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Cellular Uptake of Exogenous Human PDCD5 Protein^*

Ying Wang, Dan Li, Hui Fan, Linjie Tian, Yingcheng Zhong, Yingmei Zhang, Lan Yuan^¶, Caining Jin, Caihua Yin, and Dalong Ma¹

From the Center for Human Disease Genomics, Peking University, Beijing 100083, China and the Laboratory of Medical Immunology, School of Basic Medical Science, and ^¶Peking University Medical and Health Analysis Center, Peking University Health Science Center, Beijing 100083, China

PDCD5 (human programmed cell death 5) plays a significant role in apoptotic and paraptotic cell deaths. However, it was found that recombinant PDCD5 added exogenously to culture medium could also enhance programmed cell death triggered by certain stimuli. Here we show that PDCD5 has a remarkable role in intercellular transport in various cells (endogenous caveolin-1-positive and -negative cells) through a clathrin-independent endocytic pathway that originates from heparan sulfate proteoglycan binding and lipid rafts. These conclusions are supported by the studies of slow internalization kinetics of PDCD5 endosomes, by the resistance of endosomes to nonionic detergents, by the overexpression of the clathrin dominant negative mutant form, which did not block PDCD5-fluorescein isothiocyanate uptake, and by PDCD5 localization in lipid rafts by immunofluorescence, electron microscopy techniques, and sucrose density centrifugation. This is further supported by the findings that certain drugs that disrupt lipid rafts, compete with cell membrane heparan sulfate proteoglycans, or block the caveolae pathway, impair the PDCD5 internalization process. The translocation activity of PDCD5 may possess physiological significance and be a potential mechanism for its programmed cell death-promoting activity. PDCD5 protein also has the ability to drive the internalization of large protein cargo, depending on the residues 109-115 mapped by deletion mutagenesis, and can introduce the Mdm-2 binding domain of human p53 into living cells to induce cell death in human cancer cells, indicating that PDCD5 may serve as a vehicle and thus have potential in the field of protein delivery to the cells. This is the first evidence of such findings.

Received for publication, January 9, 2006 , and in revised form, May 1, 2006.

^* This work was supported by State Key Program of Basic Research (973) Grant G2000056909 and National High Technology Research and Development Program of China Grant 2002BA711A01. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Video 1.

¹ To whom correspondence should be addressed: Center for Human Disease Genomics, Peking University, 38 Xueyuan Rd., Beijing 100083, China. Tel.: 8610-82801149; Fax: 8610-82801149; E-mail: madl{at}bjmu.edu.cn.

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