Hyperosmotic Shock Engages Two Positive Feedback Loops through Caspase-3-dependent Proteolysis of JNK1-2 and Bid.
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 activated early by osmostress, and sustained activation of both isoforms accelerates the apoptotic program. When caspase-3 is activated, JNK1-2 is proteolyzed at Asp-385 increasing the release of cytochrome c and caspase-3 activity, thereby 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 bi-ubiquitinated. Caspase-3 activation by hyperosmotic shock induces proteolysis of Bid and mono-ubiquitinated Bid at Asp-52 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.
From the Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica, Facultad de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
Jicheng
J
Yue
From the Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica, Facultad de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain.
Nabil
N
Ben Messaoud
From the Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica, Facultad de Medicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain josemanuel.lopez@uab.cat.
José M
JM
López
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism*; D009997:Osmotic Pressure / Q000502:physiology*; D059748:Proteolysis; D015398:Signal Transduction; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D051017:Apoptosis Regulatory Proteins; C541383:Bid protein, Xenopus; D007527:Isoenzymes; D029867:Xenopus Proteins; D048055:Mitogen-Activated Protein Kinase 8; D053148:Caspase 3
Bid; apoptosis; c-Jun N-terminal kinase (JNK); oocyte; osmostress; protein kinase; signaling; ubiquitylation (ubiquitination)