AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

Abstract

SummaryCell death has been initially divided into apoptosis, in which the cell plays an active role, and necrosis, which is considered a passive cell death program. Intense research performed in the last decades has concluded that ''programmed'' cell death (PCD) is a more complex physiological process than initially thought. Indeed, although in most cases the PCD process is achieved via a family of Cys proteases known as caspases, an important number of regulated PCD pathways do not involve this family of proteases. As a consequence, active forms of PCD are initially referred to as caspase-dependent and caspase-independent. More recent data has revealed that there are also active caspase-independent necrotic pathways defined as necroptosis (programmed necrosis). The existence of necroptotic forms of death was corroborated by the discovery of key executioners such as the kinase RIP1 or the mitochondrial protein apoptosis-inducing factor (AIF). AIF is a Janus protein with a redox activity in the mitochondria and a pro-apoptotic function in the nucleus. We have recently described a particular form of AIF-mediated caspase-independent necroptosis that also implicates other molecules such as PARP-1, calpains, Bax, Bcl-2, histone H2AX, and cyclophilin A. From a therapeutic point of view, the unraveling of this new form of PCD poses a question: is it possible to modulate this necroptotic pathway independently of the classical apoptotic paths? Because the answer is yes, a wider understanding of AIF-mediated necroptosis could theoretically pave the way for the development of new drugs that modulate PCD. To this end, we present here an overview of the current knowledge of AIF and AIF-mediated necroptosis. We also summarize the state of the art in some of the most interesting therapeutic strategies that could target AIF or the AIF-mediated necroptotic pathway.

La mort cellulaire programmée ne manque pas de vocabulaire

“…L'hyperactivation de PARP-1 a de multiples conséquences, telles que l'épuisement des stocks d'ATP intracellulaire, l'activation des protéases dépendantes du calcium (calpaïnes), la libération de polymères de PAR et l'induction de la perméabilité mitochondriale [15]. Ces étapes précédentes contribuent à la sortie de l'effecteur mitochondrial de mort cellulaire AIF, qui, une fois relocalisé dans le noyau, fragmente l'ADN [16]. Cette voie de nécrose dépendante de PARP-1 a également été démontrée comme dépendante des kinases RIP1 et RIP3, soulevant la question d'une nécroptose intrinsèque, en opposition à la nécroptose extrinsèque induite par les récepteurs de mort.…”

Anti-CHMP5 single chain variable fragment antibody retrovirus infection induces programmed cell death of AML leukemic cells in vitro

“…Although the apoptosis-inducing protein, AIF, increased after scFv retrovirus infection, AIF is thought to activiate Caspase-independent necrotic PCD pathways. That is, it is considered to be unable to active Caspase 3 [32,33] . It appears that an additional uncommon Caspase-dependent apoptotic PCD pathway is activated, or this may indicate that AIF can active Caspase 3.…”

“…AIF-induced apoptosis now is reported to be Caspaseindependent necroptosis [32] , and necrosis is thought to be type III programmed cell death [30] . Increasing evidence shows that necrosis is a highly orchestrated type of PCD [32,33] .…”

“…Increasing evidence shows that necrosis is a highly orchestrated type of PCD [32,33] . Upon activation of PCD, AIF is released from the mitochondria and translocated into the nucleus to induce phosphatidylserine exposure, chromatin condensation and DNA fragmenta tion [27,28] .…”

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

“…The exact mechanism by which RIP1-RIP3 enforces necroptosis remains to be elucidated although the involvement of ROS (reactive oxygen species) production, lysosomal membrane permeabilisation, apoptosisinducing factor and PARP has been implicated (Vercammen et al, 1998b;Lin et al, 2004;Vandenabeele et al, 2010;Delavallee et al, 2011).…”