Endoplasmic Reticulum Stress-induced Apoptosis in Leishmania through Ca2�-dependent and Caspase-independent Mechanism*

Dolai, Subhankar and Pal, Swati and Yadav, Rajesh K and Adak, Subrata (2011) Endoplasmic Reticulum Stress-induced Apoptosis in Leishmania through Ca2�-dependent and Caspase-independent Mechanism*. The Journal of Biological Chemistry, 286 (15). pp. 13638-13646.

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    Abstract

    Numerous reports have shown that mitochondrial dysfunctions play a major role in apoptosis of Leishmania parasites, but the endoplasmic reticulum (ER) stress-induced apoptosis in Leishmania remains largely unknown. In this study, we investigate ER stress-induced apoptotic pathways in Leishmania major using tunicamycin as an ER stress inducer. ER stress activates the expression of ER-localized chaperone protein BIP/GRP78 (binding protein/identical to the 78-kDa glucose-regulated protein) with concomitant generation of intracellular reactive oxygen species. Upon exposure to ER stress, the elevation of cytosolic Ca2� level is observed due to release of Ca2� from internal stores. Increase in cytosolic Ca2� causes mitochondrial membrane potential depolarization and ATP loss as ablation of Ca2� by blocking voltage-gated cation channels with verapamil preserves mitochondrial membrane potential and cellular ATP content. Furthermore, ER stress-induced reactive oxygen species (ROS)-dependent release of cytochrome c and endonuclease G from mitochondria to cytosol and subsequent translocation of endonuclease G to nucleus are observed. Inhibition of caspase-like proteases with the caspase inhibitor benzyloxycarbonyl- VAD-fluoromethyl ketone or metacaspase inhibitor antipain does not prevent nuclear DNA fragmentation and phosphatidylserine exposure. Conversely, significant protection in tunicamycin-induced DNA degradation and phosphatidylserine exposure was achieved by either pretreatment of antioxidants (N-acetyl-L-cysteine, GSH, and L-cysteine), chemical chaperone (4-phenylbutyric acid), or addition of Ca2� chelator (1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acidacetoxymethyl ester). Taken together, these data strongly demonstrate that ER stress-induced apoptosis in L. major is dependent on ROS and Ca2�-induced mitochondrial toxicity but independent of caspase-like proteases.

    Item Type: Article
    URI: http://www.eprints.iicb.res.in/id/eprint/91
    Subjects: Structural Biology & Bioinformatics
    Divisions: Indian Institute of Chemical Biology
    Depositing User: Ms Sutapa Ganguly
    Date Deposited: 28 Sep 2011 13:03
    Last Modified: 20 Jan 2012 11:01
    Official URL: http://dx.doi.org/10.1074/jbc.M110.201889
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