title: Fas apoptosis inhibitory molecules: more than death-receptor antagonists in the nervous system.
abstract: The importance of death receptor (DR) signaling in embryonic development and physiological homeostasis is well established, as is the existence of several molecules that modulate DRs function, among them Fas Apoptotis Inhibitory Molecules. Although FAIM1, FAIM2, and FAIM3 inhibit Fas-induced cell death, they are not structurally related, nor do they share expression patterns. Moreover, they inhibit apoptosis through completely different mechanisms. FAIM1 and FAIM2 protect neurons from DR-induced apoptosis and are involved in neurite outgrowth and neuronal plasticity. FAIM1 inhibits Fas ligand- and tumor necrosis factor alpha-induced apoptosis by direct interaction with Fas receptor and through the stabilization of levels of X-linked inhibitor of apoptosis protein, a potent anti-apoptotic protein that inhibits caspases. Low FAIM1 levels are found in Alzheimer's disease, thus sensitizing neurons to tumor necrosis factor alpha and prompting neuronal loss. FAIM2 protects from Fas by direct interaction with Fas receptor, as well as by modulating calcium release at the endoplasmic reticulum through interaction with Bcl-xL. Several studies prove the role of FAIM2 in diseases of the nervous system, such as ischemia, bacterial meningitis, and neuroblastoma. The less characterized member of the FAIM family is FAIM3, which is expressed in tissues of the digestive and urinary tracts, bone marrow and testes, and restricted to the cerebellum in the nervous system. FAIM3 protects against DR-induced apoptosis by inducing the expression of other DR-antagonists such as CFLAR or through the interaction with the DR-adaptor protein Fas-associated via death domain. FAIM3 null mouse models reveal this protein as an important mediator of inflammatory autoimmune responses such as those triggered in autoimmune encephalomyelitis. Given the differences between FAIMs and the variety of processes in which they are involved, here we sought to provide a concise review about these molecules and their roles in the physiology and pathology of the nervous system. Even though they share name and inhibit Fas-induced cell death, Fas apoptotic inhibitory molecules (FAIMs) are not structurally related and inhibit apoptosis through completely different mechanisms. In this review, we describe FAIM1, FAIM2, and FAIM3 functions in the nervous system, and their implication in diverse pathologies such as neurodegenerative disease, cancer, or autoimmune diseases.
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain.|Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Planells-Ferrer
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain.|Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Urresti
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain.|Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Coccia
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain.|Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Koen M O
authors.initials: KM
authors.lastname: Galenkamp
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain.|Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Calleja-Yagüe
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain.|Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: López-Soriano
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain.|Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Paulina
authors.initials: P
authors.lastname: Carriba
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain. bruna.barneda@vhir.org.|Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. bruna.barneda@vhir.org.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. bruna.barneda@vhir.org.
authors.forename: Bruna
authors.initials: B
authors.lastname: Barneda-Zahonero
authors.affiliation: Group of Translational Research in Childhood and Adolescent Cancer, Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain. miguel.segura@vhir.org.
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Segura
authors.affiliation: Cell Signaling and Apoptosis Group, Institut de Recerca de l'Hospital Universitari de la Vall d'Hebron (VHIR), Barcelona, Spain. joan.comella@vhir.org.|Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. joan.comella@vhir.org.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. joan.comella@vhir.org.
authors.forename: Joan X
authors.initials: JX
authors.lastname: Comella
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D051379:Mice; D009420:Nervous System; D019014:fas Receptor / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C421307:FAIM protein, human; D019014:fas Receptor
keywords: FAIM; TOSO; apoptosis; lifeguard; nervous system