Protein degradation and apoptosis

Ubiquitination and proteasomal degradation represent the major protein degradation pathway in the cell. Two classes of ubiquitin enzymes, E2 ubiquitin-conjugating enzyme UbcH7 [25] and the E3 ubiquitin ligase protein parkin [15,130] or HDM3 [131], were found to be S-nitrosated. S-nitrosation of the target protein may also change its sensitivity to ubiquitination and proteasomal degradation [132]. By contrast, S-nitrosation of iron regulatory protein 2 promotes its ubiquitination and proteasomal degradation [133]. Interestingly, a recent study shows that S-nitrosation of GAPDH augments its binding and stability, as well as promotes nuclear translocation of the ubiquitin ligase Siah1, facilitating its degradation of nuclear proteins [134]. Recently, nitric oxide has been shown to increase HIF-1 and p53 stability by preventing their proteasomal degradation [135-138].

Beginning in 1997, several studies showed that one mechanism by which NO exerts its antiapoptotic effect is by S-nitrosation of the reactive cysteine of caspases [139-141]. It has also been shown that most of the caspases can be S-nitrosated, with the consequent inhibition of their enzymatic activity [82]. The inhibition of S-nitrosated caspases could be reversed by denitrosation, which is induced by two activators of apoptosis, Fas ligand and TNFa [142,143]. In another study, thioredoxin was shown to catalyze S-nitrosation of the caspase 3 active site cysteine [144]. S-nitrosation may also inhibit the caspase-recruitment domain (CARD) interactions between Apaf-1 and procaspase, preventing apoptosome formation and the sequential caspase cascade [145].

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