FAIM-L - SIVA-1: Two Modulators of XIAP in Non-Apoptotic Caspase Function

Abstract

Apoptosis is crucial for the correct development of the nervous system. In adulthood, the same protein machinery involved in programmed cell death can control neuronal adaptiveness through modulation of synaptic pruning and synaptic plasticity processes. Caspases are the main executioners in these molecular pathways, and their strict regulation is essential to perform neuronal remodeling preserving cell survival. FAIM-L and SIVA-1 are regulators of caspase activation. In this review we will focus on FAIM-L and SIVA-1 as two functional antagonists that modulate non-apoptotic caspase activity in neurons. Their participation in long-term depression and neurite pruning will be described in base of the latest studies performed. In addition, the association of FAIM-L non-apoptotic functions with the neurodegeneration process will be reviewed.

Keywords: Alzheimer's disease; XIAP antagonist; axon remodeling; pruning; synaptic plasticity (LTP/LTD).

FIGURE 1

Participation of FAIM-L and SIVA-1 in neuronal plasticity processes. The upper panel diagram represents the molecular mechanism by which FAIM-L and SIVA-1 are involved in AMPA receptors internalization during LTD processes in synaptic plasticity, in response to NMDA stimulation. The maintenance of XIAP-FAIM-L interaction would allow XIAP-mediated caspase-3 inhibition, and therefore prevent the caspase-3-dependent AMPA receptors internalization; a displacement of this interaction mediated by SIVA-1 binding to FAIM-L would allow the activation of caspase-3 and its consequent LTD induction and synaptic weakening. The lower panel diagram shows the similar role of FAIM-L and SIVA-1 in axonal pruning, as in trophic factors deprivation. In this case, an upstream activation of the mitochondrial apoptotic machinery would converge in the activation of caspase-3, whose activity would be regulated by the balance between SIVA-1-FAIM-L or XIAP-FAIM-L binding.