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SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist FAIM-L Coccia, Elena Planells Ferrer, Laura Badillos Rodríguez, Raquel Pascual Sánchez, Marta Segura, Miguel F. Fernández Hernández, Rita López Soriano, Joaquin Garí, Eloi Soriano García, Eduardo Barneda Zahonero, Bruna Moubarak, Rana S. Pérez García, M. Jose Comella i Carnicé, Joan Xavier, 1963- Apoptosi Neurociències Apoptosis Neurosciences 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. 2020-05-13T10:50:16Z 2020-05-13T10:50:16Z 2020-02-03 2020-05-13T10:50:16Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 2041-4889 https://hdl.handle.net/2445/159980 699819 32015347 eng Reproducció del document publicat a: https://doi.org/10.1038/s41419-020-2282-x Cell Death and Disease, 2020, vol. 11, num. 2, p. 82 https://doi.org/10.1038/s41419-020-2282-x cc-by-nc-sa (c) Coccia, Elena et al., 2020 http://creativecommons.org/licenses/by-nc-sa/3.0/es info:eu-repo/semantics/openAccess 19 p. application/pdf Nature Publishing Group Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)