title: FAIM-L is an IAP-binding protein that inhibits XIAP ubiquitinylation and protects from Fas-induced apoptosis.
abstract: The neuronal long isoform of Fas Apoptotic Inhibitory Molecule (FAIM-L) protects from death receptor (DR)-induced apoptosis, yet its mechanism of protection remains unknown. Here, we show that FAIM-L protects rat neuronal Type II cells from Fas-induced apoptosis. XIAP has previously emerged as a molecular discriminator that is upregulated in Type II and downregulated in Type I apoptotic signaling. We demonstrate that FAIM-L requires sustained endogenous levels of XIAP to protect Type II cells as well as murine cortical neurons from Fas-induced apoptosis. FAIM-L interacts with the BIR2 domain of XIAP through an IAP-binding motif, the mutation of which impairs the antiapoptotic function of FAIM-L. Finally, we report that FAIM-L inhibits XIAP auto-ubiquitinylation and maintains its stability, thus conferring protection from apoptosis. Our results bring new understanding of the regulation of endogenous XIAP by a DR antagonist, pointing out at FAIM-L as a promising therapeutic tool for protection from apoptosis in pathological situations where XIAP levels are decreased.
authors.affiliation: Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), 08035 Barcelona, Spain, Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra Spain, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Spain, Departament de Ciències Experimentals i de la Salut, Cell Signalling Unit, Universitat Pompeu Fabra, 08003 Barcelona, Spain, Laboratoris Clinics, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain, and Institut de Recerca Biomèdica de Lleida, Universitat de Lleida, 25198 Lleida, Spain.
authors.forename: Rana S
authors.initials: RS
authors.lastname: Moubarak
authors.forename: Laura
authors.initials: L
authors.lastname: Planells-Ferrer
authors.forename: Jorge
authors.initials: J
authors.lastname: Urresti
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Reix
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Segura
authors.forename: Paulina
authors.initials: P
authors.lastname: Carriba
authors.forename: Fernando
authors.initials: F
authors.lastname: Marqués-Fernàndez
authors.forename: Carme
authors.initials: C
authors.lastname: Sole
authors.forename: Nuria
authors.initials: N
authors.lastname: Llecha-Cano
authors.forename: Joaquin
authors.initials: J
authors.lastname: Lopez-Soriano
authors.forename: Daniel
authors.initials: D
authors.lastname: Sanchis
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Yuste
authors.forename: Joan X
authors.initials: JX
authors.lastname: Comella
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D018696:Neuroprotective Agents; D016716:PC12 Cells; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D054875:Ubiquitination / Q000187:drug effects*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C489013:DIABLO protein, rat; C586050:FAIM protein, rat; D051034:Inhibitor of Apoptosis Proteins; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D051636:X-Linked Inhibitor of Apoptosis Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D045304:Cytochromes c; D020169:Caspases