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.

Details

Title
SIVA-1 regulates apoptosis and synaptic function by modulating XIAP interaction with the death receptor antagonist FAIM-L
Author
Coccia, Elena 1   VIAFID ORCID Logo  ; Planells-Ferrer, Laura 1 ; Badillos-Rodríguez Raquel 1 ; Pascual, Marta 2 ; Segura, Miguel F 3   VIAFID ORCID Logo  ; Fernández-Hernández, Rita 4 ; López-Soriano Joaquin 1 ; Garí Eloi 4 ; Soriano, Eduardo 5 ; Barneda-Zahonero Bruna 1 ; Moubarak, Rana S 6   VIAFID ORCID Logo  ; Jose, Pérez-García M 1   VIAFID ORCID Logo  ; Comella, Joan X 1   VIAFID ORCID Logo 

 Cell Signaling and Apoptosis Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain (GRID:grid.430994.3) (ISNI:0000 0004 1763 0287); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Universitat Autònoma de Barcelona, Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Bellaterra, Spain (GRID:grid.7080.f) 
 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Institut de Neurociències, Universitat de Barcelona, Bellaterra, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247); Institut de Neurociències, Universitat de Barcelona, Department of Cell Biology, Physiology and Immunology, Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247) 
 Group of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute (VHIR)-UAB, Barcelona, Spain (GRID:grid.430994.3) (ISNI:0000 0004 1763 0287) 
 Universitat de Lleida, Cell Cycle Laboratory, Institut de Recerca Biomèdica de Lleida (IRBLleida), and Departament de Ciències Mèdiques Bàsiques; Facultat de Medicina, Lleida, Spain (GRID:grid.15043.33) (ISNI:0000 0001 2163 1432) 
 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Institut de Neurociències, Universitat de Barcelona, Bellaterra, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247); Institut de Neurociències, Universitat de Barcelona, Department of Cell Biology, Physiology and Immunology, Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247); ICREA Academia, Barcelona, Spain (GRID:grid.425902.8) (ISNI:0000 0000 9601 989X) 
 Cell Signaling and Apoptosis Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain (GRID:grid.430994.3) (ISNI:0000 0004 1763 0287); Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Universitat Autònoma de Barcelona, Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Bellaterra, Spain (GRID:grid.7080.f); NYU Langone Health, Department of Pathology, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753) 
Publication year
2020
Publication date
Feb 2020
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2350325646
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.