Specific cleavage of p62-PKC zeta-Par-4 ternary complex during apoptotic cell death

다국어 초록 (Multilingual Abstract)

Caspases are activated during apoptosis and proteolytically degrade many cytoplasmic proteins, thereby playa central role in the execution of apoptosis. PKC zeta has been recognized as an important mediator of a survival signaling process, and separately reported to associate with p62 or with par-4. Here, we demonstrates that PKC zeta, p62, and par-4 form a ternary complex and that all three molecules are specifically cleaved during apoptotic cell death. The physiological roles of the ternary complex and its individual components are yet understood well. A multiubiquitin chain binding protein p62 seems to play an important role in sequestration of cytosolic proteasome-targeting proteins and, thus, to initiate the formation of cytosolic inclusion bodies. In addition, p62 modulates the NFĸB-mediated survival signaling through interactions with PKC zeta, RIP and some TRAF family members. On the other hand, par-4(prostate apoptosis response 4) interacts with PKC zeta and inhibits its enzymatic activity, resulting in apoptosis of several cell lines thus far tested. Moreover, the incresed levels of p62 and par-4 in neurons of Alzheimer disease and ALS patients implies that these proteins are closely related to neuro-degenerative disorders caused by neuronal apoptosis. It has been found that two and one caspase target sites are present in p62 and par-4 respectively and that the major executor of these cleavages is caspase-6. Overexpression of the non-cleavable mutant of p62 increases the viability of cells and simultaneously formes intracytoplasmic inclusions. And the cleavage of par-4 seems to trigger or enhance the apoptotic activity of par-4. In the current presentation, the role of the p62-PKC zeta-par-4 ternary complex in cell death and survival signaling and its relevance to neuro-degeneration will be hypothesized and discussed.