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J. Biol. Chem., Vol. 280, Issue 49, 40985-40995, December 9, 2005

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The Lysosome-associated Apoptosis-inducing Protein Containing the Pleckstrin Homology (PH) and FYVE Domains (LAPF), Representative of a Novel Family of PH and FYVE Domain-containing Proteins, Induces Caspase-independent Apoptosis via the Lysosomal-Mitochondrial Pathway^*

Wei Chen, Nan Li, Taoyong Chen, Yanmei Han, Changfei Li, Yuzhen Wang, Weigang He, Lihuang Zhang, Tao Wan, and Xuetao Cao1

From the Institute of Immunology, Zhejiang University, 353 Yanan Road, Hangzhou 310031, Zhejiang, China and the Institute of Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China

Lysosomes have recently been identified as important apoptotic signal integrators in response to various stimuli. Here we report the functional characterization of LAPF, a novel lysosome-associated apoptosis-inducing protein containing PH and FYVE domains. LAPF is a representative of a new protein family, the Phafins (protein containing both PH and FYVE domains), which consists of 14 unidentified proteins from various species. Overexpression of LAPF in L929 cells induces apoptosis and also increases cell sensitivity to TNF-induced apoptosis, concomitant with its translocation to lysosomes. Two mutants of LAPF, either lacking the PH or FYVE domain, failed to induce cell death and translocate to lysosomes, suggesting that both domains are required for its apoptosis-inducing activity and relocation. We demonstrate that LAPF may induce apoptosis via the following steps: LAPF translocation to lysosomes, lysosomal membrane permeabilization (LMP), release of cathepsin (cath) D and L, mitochondrial membrane permeabilization (MMP), release of apoptosis-inducing factor (AIF), and caspase-independent apoptosis. The cath D-specific inhibitor attenuates LAPF-induced apoptosis, indicating a pivotal role of lysosomes in LAPF-initiated apoptosis. We also demonstrate that the lysosomal pathway was employed in the typical apoptotic model in which high dose TNF was used to stimulate L929 cells. Silencing of LAPF expression by small RNA interference protected L929 cells from hTNF-induced apoptosis by impairing hTNF-triggered LMP and MMP. Therefore, LAPF may launch caspase-independent apoptosis through the lysosomal-mitochondrial pathway.

Received for publication, February 25, 2005 , and in revised form, July 11, 2005.

The nucleotide sequence reported in this paper has been submitted to the DDBJ/Gen-Bank/EB1 Data Bank with accession number AY037145 [GenBank] .

^* This work was supported by National Natural Science Foundation Grant 30121002, National Key Basic Research Program Grant 2001CB510002, National High Biotechnology Development Program Grant 2002BA711A01, and Shanghai Science Technology Project O3QD14068. 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: Inst. of Immunology, Zhejiang University, 353 Yanan Rd., Hangzhou 310031, Zhejiang, China. Tel.: 86-571-8721-7151; Fax: 86-571-8721-7329; E-mail: caoxt{at}public3.sta.net.cn.

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