The Apoptosis Inducing Factor in cell death: past its key role in the assembly of the degradosome

Gracia Lostao, Ana Isabel
XI National Conference BIFI
Participation type: 
Other authors: 
Novo N, Romero-Tamayo S, Marcuello C, Boneta S, Blasco-Machin I, Velázquez-Campoy A, Villanueva R, Moreno-Loshuertos R, Lostao A, Medina M and Ferreira P

The Apoptosis Inducing Factor (AIF) is a moonlighting flavoprotein that contributes to
the assembly of the mitochondrial respiratory complexes in healthy cells, but which is
also able to trigger DNA cleavage and parthanatos. In response to apoptotic stimuli,
AIF redistributes from the mitochondria to the cytosol, where upon association with
endonuclease cyclophilin A (CypA) the optimal nuclear translocation of both proteins is
favoured. In the nucleus, the AIF:CypA complex is proposed to recruit histone H2AX,
leading to the formation of a ternary complex known as the “degradosome”. This
complex has the capacity to bind DNA, inducing chromatin condensation and DNA
degradation in a caspase–independent manner. Here, we provide evidence for the
molecular assembly of such complex, as well as for the cooperative effects among its
protein components to degrade genomic DNA into large fragments. Furthermore, we
present binding studies showing that all DNA-degradosome components are able to
produce binary and ternary interactions, envisaging binding cooperativity. Altogether
these data evidence for the first time at the molecular level the simultaneous interplay
of AIFΔ101 with all components of the DNA-degradosome complex, as well as pointing to
some features that potentially contribute to its assembly in the cell.