Caspase-3/Sandbox: Difference between revisions
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=====S-Nitrosylation===== | =====S-Nitrosylation===== | ||
An ambient level of nitric oxide has antiapoptotic effects via S-nitrosylation of caspase-3 zymogens at its catalytic Cys163 residue perhaps because it directly associates with all 3 NOS isoforms. S-nitrosylation effectively inhibits the enzyme activity of caspase-3 (Mannick, 2007). NO and S-nitrosoglutathione (GSNO) reacts nonspecifically to all cysteine residues of caspase-3 (Mitchell, 2005). Caspase-3 nitrosylation at a second cysteine residue (Cys47, Cys220, or Cys 264) may have further antiapoptotic effects by leading to its association with acid sphingomyelinase (ASM). ASM inhibits cleavage and activation of caspase-3 by initiator caspases, such as caspase-8 and caspase-9 (Mannick, 2007). | An ambient level of nitric oxide has antiapoptotic effects via S-nitrosylation of caspase-3 zymogens at its catalytic Cys163 residue perhaps because it directly associates with all 3 NOS isoforms. S-nitrosylation effectively inhibits the enzyme activity of caspase-3 (Mannick, 2007). NO and S-nitrosoglutathione (GSNO) reacts nonspecifically to all cysteine residues of caspase-3 (Mitchell, 2005). Caspase-3 nitrosylation at a second cysteine residue (Cys47, Cys220, or Cys 264) may have further antiapoptotic effects by leading to its association with acid sphingomyelinase (ASM). ASM inhibits cleavage and activation of caspase-3 by initiator caspases, such as caspase-8 and caspase-9 (Mannick, 2007). | ||
Thioredoxin, the main intracellular oxidoreductase, does not inhibit caspase-3 activity. However, Trx-Cys73-SNO inhibits apoptosis by decreasing caspase-3 activity via transnitrosylation at Cys163 catalytic residue. This reaction is reversible, although this is not as likely since Cys163 on caspase-3 is more nucleophilic than Cys73 on Trx. GSNO is capable of transferring its nitroso-group to Trx-Cys73, which in turn can S-nitrosylate caspase-3, leading to inactive caspase-3 (Mitchell, 2005). | Thioredoxin, the main intracellular oxidoreductase, does not inhibit caspase-3 activity. However, Trx-Cys73-SNO inhibits apoptosis by decreasing caspase-3 activity via transnitrosylation at Cys163 catalytic residue. This reaction is reversible, although this is not as likely since Cys163 on caspase-3 is more nucleophilic than Cys73 on Trx. GSNO is capable of transferring its nitroso-group to Trx-Cys73, which in turn can S-nitrosylate caspase-3, leading to inactive caspase-3 (Mitchell, 2005). | ||
[[Image:Mech of sno transfer.png|600px|center]] | |||
In human B- and T-cell lines, nitrosylation of caspase-3 depends on localization: mitochondrial but not cytoplasmic caspase-3 zymogens are S-nitrosylated. S-nitrosylation may prevent improper autoactivation in the mitochondria due to close proximity in the intermembrane space (Mannick, 2001). Mitochondrial caspase-3 is released into the cytoplasm and becomes denitrosylated when FasL binds Fas receptor (Mannick, 2001). Fas receptor activation by FasL activates the extrinsic pathway of apoptosis through activation of caspase-8, which can either directly cleave procaspase-3 to caspase-3 or lead to Bid cleavage to tBid. tBID then permeates into the mitochondria, leading to cytochrome c release, apoptosome formation with caspase-9, and finally caspase-3 cleavage to its activated form. Smac/DIABLO is also released from the mitochondria and leads to inhibition of XIAP (X-linked inhibitor of apoptosis), abrogating its inhibitory effect on caspase-3 activity within the cytosol. XIAP also functions as an E3 ubiquitin ligase, targeting caspase-3 for proteasomal degradation (Nakamura, 2010). Aside from this, Fas-induced apoptosis also leads to denitrosylation of caspase-3 and therefore activation by freeing its catalytic Cys residue (Mannick, 1999). Perhaps, this denitrosylation occurs via transnitrosylation of XIAP RING domain at Cys450, which in effect inhibits its E3 ligase activity. This further prolongs caspase-3 activity by blocking its degradation, and thus promotes increased cell death (Nakamura, 2010). Thus, S-nitrosylation of caspases inhibits caspase activation and apoptosis, whereas denitrosylation activates caspases and promotes apoptosis (Mannick, 2007). | In human B- and T-cell lines, nitrosylation of caspase-3 depends on localization: mitochondrial but not cytoplasmic caspase-3 zymogens are S-nitrosylated. S-nitrosylation may prevent improper autoactivation in the mitochondria due to close proximity in the intermembrane space (Mannick, 2001). Mitochondrial caspase-3 is released into the cytoplasm and becomes denitrosylated when FasL binds Fas receptor (Mannick, 2001). Fas receptor activation by FasL activates the extrinsic pathway of apoptosis through activation of caspase-8, which can either directly cleave procaspase-3 to caspase-3 or lead to Bid cleavage to tBid. tBID then permeates into the mitochondria, leading to cytochrome c release, apoptosome formation with caspase-9, and finally caspase-3 cleavage to its activated form. Smac/DIABLO is also released from the mitochondria and leads to inhibition of XIAP (X-linked inhibitor of apoptosis), abrogating its inhibitory effect on caspase-3 activity within the cytosol. XIAP also functions as an E3 ubiquitin ligase, targeting caspase-3 for proteasomal degradation (Nakamura, 2010). Aside from this, Fas-induced apoptosis also leads to denitrosylation of caspase-3 and therefore activation by freeing its catalytic Cys residue (Mannick, 1999). Perhaps, this denitrosylation occurs via transnitrosylation of XIAP RING domain at Cys450, which in effect inhibits its E3 ligase activity. This further prolongs caspase-3 activity by blocking its degradation, and thus promotes increased cell death (Nakamura, 2010). Thus, S-nitrosylation of caspases inhibits caspase activation and apoptosis, whereas denitrosylation activates caspases and promotes apoptosis (Mannick, 2007). | ||