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

• Published in: Cell death & disease Vol. 11; no. 2; p. 82
• Main Authors: Coccia, Elena, Planells-Ferrer, Laura, Badillos-Rodríguez, Raquel, Pascual, Marta, Segura, Miguel F, Fernández-Hernández, Rita, López-Soriano, Joaquin, Garí, Eloi, Soriano, Eduardo, Barneda-Zahonero, Bruna, Moubarak, Rana S, Pérez-García, M Jose, Comella, Joan X
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 03.02.2020; Nature Publishing Group UK
• Subjects: Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Caspase 3 - metabolism; Caspase-3; Cell death; Cells, Cultured; Endocytosis; HEK293 Cells; Hippocampus; Hippocampus - cytology; Hippocampus - metabolism; Humans; IAP protein; Inhibitor of Apoptosis Proteins - metabolism; Internalization; Long-term depression; Mice; N-Methylaspartate - pharmacology; Neuronal Plasticity; Neurons - drug effects; Neurons - metabolism; PC12 Cells; Plasticity (neural); Proteasomes; Protein Binding; Rats; Receptors, AMPA - metabolism; Ubiquitin; Ubiquitination; XIAP protein; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2282-x

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.