Endoplasmic Reticulum Stress-induced Apoptosis in Leishmania through Ca2�-dependent and Caspase-independent Mechanism*
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
Endoplasmic Reticulum Stress-induced Apoptosis in Leishmania
through Ca2�-dependent and Caspase-independent
Mechanism*
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| Creator |
Dolai, Subhankar
Pal, Swati Yadav, Rajesh K Adak, Subrata |
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| Subject |
Structural Biology & Bioinformatics
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| Description |
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.
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| Publisher |
American Society for Biochemistry and Molecular Biology
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| Date |
2011
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/91/1/[64].pdf
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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| Relation |
http://dx.doi.org/10.1074/jbc.M110.201889
http://www.eprints.iicb.res.in/91/ |
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