El paper de siva-1 en neuronesun nou antagonista funcional de faim-l

Resumen

Apoptosis is the main type of programmed cell death, essential for the correct development of nervous system. Even if in adult neurons apoptosis has been related to the pathology of neurodegenerative diseases, apoptotic machinery activation has been also described as necessary in non-lethal regulatory events, such as synaptic plasticity and axonal pruning. Apoptosis activation, which culminates with engagement of effector caspases, is modulated by hundreds of proteins. One of the regulators of apoptosis is the long isoform of Fas Apoptosis Inhibitory Molecule (FAIM-L), a neuronal specific death receptor antagonist shown capable to modulate neuronal caspase activation. FAIM-L carries out its anti-apoptotic activity by binding to X-linked Inhibitor of Apoptosis Protein (XIAP). XIAP is an inhibitor of caspases, and its levels are modulated by the ubiquitin-proteasome pathway. FAIM-L interaction with XIAP prevents its ubiquitination and degradation, allowing therefore its anti-apoptotic activity. This interaction also modulates non-apoptotic functions of caspases, such as the endocytosis of AMPA receptor (AMPAR), the main mechanism in long-term depression (LTD), and axonal pruning. To date consensus binding motifs of FAIM-L, which could shed light on its molecular mechanism of action, are unknown. Our group performed a two-hybrid screening to discover novel FAIM-L-interacting proteins. We found a functional interaction of SIVA-1 with FAIM-L. SIVA-1 is a protein described as pro-apoptotic and able to interact with XIAP. In this work we show that SIVA-1 modulates FAIM-L function by disrupting the interaction of FAIM-L with XIAP, thereby promoting XIAP ubiquitination. By modulating the inhibitors of apoptosis XIAP and FAIM-L, SIVA-1 induces caspase-dependent neuronal cell death. Furthermore, we show SIVA-1 to be a novel modulator of synaptic plasticity. After induction of LTD in an in vitro neuronal model, SIVA-1 protein levels are rapidly increased, and SIVA-1 overexpression is sufficient to induce caspase-dependent internalization of AMPAR. SIVA-1 increase is also present during axonal pruning, and SIVA-1 overexpression accelerates the degeneration process. In summary, our studies uncover a new functional partner of FAIM-L, SIVA-1. We propose SIVA-1 as a caspase modulator in neurons, and therefore to be a crucial regulator in neuronal cell death and plasticity.