Hyperosmotic Shock Engages Two Positive Feedback Loops Through Caspase-3 Dependent Proteolysis of JNK1-2 and Bid [Signal Transduction]

October 28th, 2015 by Yue, J., Ben Messaoud, N., Lopez, J. M.

Hyperosmotic shock induces early calpain activation, Smac/DIABLO release from the mitochondria and p38/JNK activation in Xenopus oocytes. These pathways regulate late cytochrome c release and caspase-3 activation. Here we show that JNK1-1 and JNK1-2 are early activated by osmostress and sustained activation of both isoforms accelerates the apoptotic program. When caspase-3 is activated JNK1-2 is proteolyzed at Asp385 increasing the release of cytochrome c and caspase-3 activity, and therefore creating a positive feedback loop. Expression of Bcl-xL markedly reduces hyperosmotic shock-induced apoptosis. In contrast, expression of Bid induces rapid caspase-3 activation, even in the absence of osmostress, which is blocked by Bcl-xL co-expression. In these conditions a significant amount of Bid in the cytosol is mono- and biubiquitinated. Caspase-3 activation by hyperosmotic shock induces proteolysis of Bid and mono-ubiquitinated Bid at Asp52 increasing the release of cytochrome c and caspase-3 activation, and thus creating a second positive feedback loop. Revealing the JNK isoforms and the loops activated by osmostress could help to design better treatments for human diseases caused by perturbations in fluid osmolarity.