SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist FAIM-L

Elena Coccia,Eloi Garí,Bruna Barneda-Zahonero,Laura Planells-Ferrer,Marta Pascual,Joaquin López-Soriano,Joan X Comella,M Jose Pérez-García,Eduardo Soriano,Rita Fernández-Hernández,Miguel F Segura,Rana S Moubarak,Raquel Badillos-Rodríguez

doi:10.1038/s41419-020-2282-x

Abstract

The long isoform of Fas apoptosis inhibitory molecule (FAIM-L) is a neuron-specific death receptor antagonist that modulates apoptotic cell death and mechanisms of neuronal plasticity. FAIM-L exerts its antiapoptotic action by binding to X-linked inhibitor of apoptosis protein (XIAP), an inhibitor of caspases, which are the main effectors of apoptosis. XIAP levels are regulated by the ubiquitin-proteasome pathway. FAIM-L interaction with XIAP prevents the ubiquitination and degradation of the latter, thereby allowing it to inhibit caspase activation. This interaction also modulates non-apoptotic functions of caspases, such as the endocytosis of AMPA receptor (AMPAR) in hippocampal long-term depression (LTD). The molecular mechanism of action exerted by FAIM-L is unclear since the consensus binding motifs are still unknown. Here, we 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 proapoptotic protein that has the capacity to interact with XIAP. We describe how SIVA-1 regulates FAIM-L function by disrupting the interaction of FAIM-L with XIAP, thereby promoting XIAP ubiquitination, caspase-3 activation and neuronal death. Furthermore, we report that SIVA-1 plays a role in receptor internalization in synapses. SIVA-1 is upregulated upon chemical LTD induction, and it modulates AMPAR internalization via non-apoptotic activation of caspases. In summary, our findings uncover SIVA-1 as new functional partner of FAIM-L and demonstrate its role as a regulator of caspase activity in synaptic function.

Highlights

Apoptosis plays a crucial role during neural development and adult life[1,2]
We found that SIVA-1 blocks the antiapoptotic function of Fas apoptosis inhibitory molecule (FAIM-L) by displacing the X-linked inhibitor of apoptosis protein (XIAP)/FAIM-L interaction, thereby inducing XIAP degradation, caspase-3 activation and subsequent neuronal death or AMPA receptor (AMPAR) internalization
SIVA-1 interacts with FAIM-L To identify the functional partners of FAIM-L, we performed a yeast-two-hybrid screening using as bait the full-length sequence of FAIM-L or the 22 N-terminal

Summary

Introduction

Apoptosis plays a crucial role during neural development and adult life[1,2]. The main orchestrators of apoptosis are caspases, effector proteases that mediate the proteolytic cascade that leads to cell death. We studied the contribution of SIVA-1 to the roles of FAIM-L and XIAP in caspase-dependent apoptotic and non-apoptotic functions in neurons. We found that SIVA-1 blocks the antiapoptotic function of FAIM-L by displacing the XIAP/FAIM-L interaction, thereby inducing XIAP degradation, caspase-3 activation and subsequent neuronal death or AMPAR internalization.

Results

Conclusion