The caspase-independent algorithm of programmed cell death in Leishmania induced by baicalein: the role of LdEndoG, LdFEN-1 and LdTatD as a DNA 'degradesome'.
In the post-genomic perspective, the quest of programmed cell death (PCD) mechanisms in kinetoplastid parasites lies in the identification and characterization of cell death executer proteins. Here, we show that baicalein (BLN), a potent topoisomerase IB inhibitor, generates an oxidative stress in the parasites leading to altered physiological and morphological parameters, which are characteristic of PCD. For the first time we elucidate that, caspase-independent activation of a novel effector molecule, endonuclease G (LdEndoG), mediates BLN-induced cell death. Functional characterization of LdEndoG identifies Flap endonuclease-1 (LdFEN-1) and LdTatD-like nuclease as other effector molecules. BLN treatment translocates LdEndoG from mitochondria to nucleus, where it forms separate complexes with LdFEN-1 and LdTatD to constitute a DNA 'degradesome' unique to these parasites. Conditional antisense knockdown of LdEndoG provides protection against PCD. This knowledge paves the path toward a better understanding of the PCD pathway in simpler systems, which could be exploited in anti-leishmanial chemotherapy.
BoseDasgupta
S
S
Molecular Parasitology Laboratory, Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, India.
Das
B B
BB
Sengupta
S
S
Ganguly
A
A
Roy
A
A
Dey
S
S
Tripathi
G
G
Dinda
B
B
Majumder
H K
HK
D000465:Algorithms; D000818:Animals; D016923:Cell Death / Q000502:physiology*; D004247:DNA / Q000378:metabolism*; D053938:DNA Fragmentation; D003851:Deoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D045585:Flap Endonucleases / Q000235:genetics / Q000378:metabolism*; D044950:Flavanones / Q000378:metabolism*; D007893:Leishmania donovani / Q000166:cytology / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D009097:Multienzyme Complexes / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D004791:Enzyme Inhibitors; D044950:Flavanones; D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C006680:baicalein; D004247:DNA; D003851:Deoxyribonucleases; D004706:Endodeoxyribonucleases; D045585:Flap Endonucleases; C052391:endonuclease G