THE PERFORIN-GRANZYME PATHWAY OF MOLECULAR MECHANISMS OF APOPTOSIS SIGNALLING PATHWAY IN APOPTOSIS
7.1.3. The perforin-granzyme pathway
Granzyme pathway is additional pathway. The Granzyme pathway induce apoptosis via either granzyme A or granzyme B. Granzymes are serine proteases that are released by cytoplasmic granules within cytotoxic T-cells and nature killer cells. This pathway activates caspase-independent cell death pathway via single standard DNA damage. This mechanism used for to kill tumor cells and virus infected cells. Cytotoxic T-cells release perforin and granzyme proteins. Perforin protein pore in the membrane of infected cells, allowing the entry of granzyme A and granzyme B. granzyme B induces activation of caspase 10 and caspase 9. Caspase 9 activates especially caspase 3. Caspase-3 acfivates CAD. CAD proceeds for DNA fragmentation and associates with apoptosis. Granzyme A form a SET complex which also induce DNA cleavage and apoptosis.
7.2. Regulation of Apoptosis :
- The IAP(inhibitors of apoptosis proteins) proteins is the most important regulators of apoptosis.
- The mammalian Bcl-2 family of anti-apoptotic genes, the homologs of ced-9 gene found in C. elegans. Bcl-2 proteins inhibit apoptosis. Bax and bak form the pore , while Bcl2, Bcl-X inhibit its formation.
- Apoptosis regulates by Hsp that is induced by stress. HSP(Hsp27, Hsp70, Hsp 90) inhibits apoptosis by inhibiting caspase-3.HSP-90 blocks the oligomerization of the Apaf-1 complex, while Hsp27 and Hsp70 block the signaling pathway from TNF-α or fas receptors.HSP-60/10 helps the activation of caspases-3.
- Apoptosis inhibit by Nitric oxide(NO) through up-regulation of kinases, like Akt. NO is combined with superoxides forming nitrogen peroxides,which are efficient initiators of the apoptotic response.Hsp90 is overexpressed by N2O2 and regulate apoptosis.
7.3. Apoptois in C. elegans
C. elegans is used as model organism to study the process of apoptosis. 131 cells of C. elegans undergo apoptosis out of 1090 cell in the embryonic stage.
The steps of apoptosis can be summarized as follows :-
- Activation of the cysteine protease ced-3 by oligomerization with ced-4.
- Apoptosis inhibitor ced-9 and the apoptosis inducer egl-1 regulate the activity of ced-3/ced-4 complex
- Ced-4 counterpart in the mammalian apoptosis is apoptotic protease activating factor 1, Apaf-1.
- Ced-3 is the single member of cysteine proteases family in C. elegans.
- Egl-1 and ced-9 are members of the Bcl-2 family of pro- or antiapoptotic proteins, respectively.