Cleavage of Atg3 protein by caspase-8 regulates autophagy during receptor-activated cell death


Oral Ö., Oz-Arslan D. , Itah Z., Naghavi A., Deveci R., Karaçalı S., ...Daha Fazla

APOPTOSIS, cilt.17, ss.810-820, 2012 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 17
  • Basım Tarihi: 2012
  • Doi Numarası: 10.1007/s10495-012-0735-0
  • Dergi Adı: APOPTOSIS
  • Sayfa Sayıları: ss.810-820

Özet

Autophagy is an evolutionarily conserved mechanism contributing to cell survival under stress conditions including nutrient and growth factor deprivation. Connections and cross-talk between cell death mechanisms and autophagy is under investigation. Here, we describe Atg3, an essential regulatory component of autophagosome biogenesis, as a new substrate of caspase-8 during receptor-mediated cell death. Both, tumor necrosis factor alpha and tumor necrosis factor-related apoptosis inducing ligand induced cell death was accompanied by Atg3 cleavage and this event was inhibited by a pan-caspase inhibitor (zVAD) or a caspase-8-specific inhibitor (zIETD). Indeed, caspase-8 overexpression led to Atg3 degradation and this event depended on caspase-8 enzymatic activity. Mutation of the caspase-8 cleavage site on Atg3 abolished its cleavage both in vitro and in vivo, demonstrating that Atg3 was a direct target of caspase-8. Autophagy was inactive during apoptosis and blockage of caspases or overexpression of a non-cleavable Atg3 protein reestablished autophagic activity upon death receptor stimulation. In this system, autophagy was important for cell survival since inhibition of autophagy increased cell death. Therefore, Atg3 provides a novel link between apoptosis and autophagy during receptor-activated cell death.