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| Pàgina inicial > Articles > Articles publicats > SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist FAIM-L |
(Hospital Universitari Vall d'Hebron. Institut de Recerca) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Universitat Autònoma de Barcelona. Institut de Neurociències) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Hospital Universitari Vall d'Hebron. Institut de Recerca)| Data: | 2020 |
| Resum: | 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. |
| Ajuts: | Ministerio de Economía y Competitividad SAF2013-47989-R Ministerio de Economía y Competitividad SAF2016-80236-R Ministerio de Economía y Competitividad CIBERNED CB06-05-1104 Ministerio de Economía y Competitividad PIE13-00027 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014SGR1609 Ministerio de Economía y Competitividad BES-2018-080846 |
| Nota: | Altres ajuts: This work was funded by grants awarded by the Spanish "Ministerio de Economía y Competitividad" , the Generalitat de Catalunya, and the Fundació La Marató de TV3 (201414-30) to J.X.C. E.C. is supported by a predoctoral fellowship from the Vall d'Hebron Research Institute (VHIR). R.B. is supported by a predoctoral fellowship from the Spanish "Ministerio de Economía y Competitividad". |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Publicat a: | Cell death and disease, Vol. 11 (february 2020) , ISSN 2041-4889 |
