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., ...More

APOPTOSIS, vol.17, pp.810-820, 2012 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 17
  • Publication Date: 2012
  • Doi Number: 10.1007/s10495-012-0735-0
  • Title of Journal : APOPTOSIS
  • Page Numbers: pp.810-820
  • Keywords: Apoptosis, Autophagy, Death receptor, TNF-alpha, TRAIL, Caspase-8, Cell survival, MEDIATED CLEAVAGE, APOPTOSIS, PROLIFERATION, FADD, IMPAIRMENT, STARVATION, CROSSTALK, MEMBRANES, SYSTEM, DOMAIN

Abstract

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.