Cytochrome c speeds up caspase cascade activation by blocking 14-3-3 epsilon-dependent Apaf-1 inhibition

Autores de CIPF

• 

  Maria Mar Orzáez Calatayud

  Autor

Participantes ajenos a CIPF

• Elena-Real, CA
• Diaz-Quintana, A
• Gonzalez-Arzola, K
• Velazquez-Campoy, A
• Lopez-Rivas, A
• Gil-Caballero, S
• De la Rosa, MA
• Diaz-Moreno, I

Grupos de Investigación

• Laboratorio de Terapias Dirigidas en Cáncer e Inflamación

  

  Jefe/a de Grupo

  Maria Mar Orzáez Calatayud

Abstract

Apoptosis is a highly regulated form of programmed cell death, essential to the development and homeostasis of multicellular organisms. Cytochrome c is a central figure in the activation of the apoptotic intrinsic pathway, thereby activating the caspase cascade through its interaction with Apaf-1. Our recent studies have revealed 14-3-3 epsilon (a direct inhibitor of Apaf-1) as a cytosolic cytochrome c target. Here we explore the cytochrome c / 14-3-3 epsilon interaction and show the ability of cytochrome c to block 14-3-3 epsilon-mediated Apaf-1 inhibition, thereby unveiling a novel function for cytochrome c as an indirect activator of caspase-9/3. We have used calorimetry, NMR spectroscopy, site mutagenesis and computational calculations to provide an insight into the structural features of the cytochrome c / 14-3-3 epsilon complex. Overall, these findings suggest an additional cytochrome c-mediated mechanism to modulate apoptosome formation, shedding light onto the rigorous apoptotic regulation network.