The long form of Fas apoptotic inhibitory molecule is expressed specifically in neurons and protects them against death receptor-triggered apoptosis.
Death receptors (DRs) and their ligands are expressed in developing nervous system. However, neurons are generally resistant to death induction through DRs and rather their activation promotes neuronal outgrowth and branching. These results suppose the existence of DRs antagonists expressed in the nervous system. Fas apoptosis inhibitory molecule (FAIM(S)) was first identified as a Fas antagonist in B-cells. Soon after, a longer alternative spliced isoform with unknown function was identified and named FAIM(L). FAIM(S) is widely expressed, including the nervous system, and we have shown previously that it promotes neuronal differentiation but it is not an anti-apoptotic molecule in this system. Here, we demonstrate that FAIM(L) is expressed specifically in neurons, and its expression is regulated during the development. Expression could be induced by NGF through the extracellular regulated kinase pathway in PC12 (pheochromocytoma cell line) cells. Contrary to FAIM(S), FAIM(L) does not increase the neurite outgrowth induced by neurotrophins and does not interfere with nuclear factor kappaB pathway activation as FAIM(S) does. Cells overexpressing FAIM(L) are resistant to apoptotic cell death induced by DRs such as Fas or tumor necrosis factor R1. Reduction of endogenous expression by small interfering RNA shows that endogenous FAIM(L) protects primary neurons from DR-induced cell death. The detailed analysis of this antagonism shows that FAIM(L) can bind to Fas receptor and prevent the activation of the initiator caspase-8 induced by Fas. In conclusion, our results indicate that FAIM(L) could be responsible for maintaining initiator caspases inactive after receptor engagement protecting neurons from the cytotoxic action of death ligands.
Segura
Miguel F
MF
Cell Signaling and Apoptosis Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida-Hospital Universitari Arnau de Vilanova, 25198 Lleida, Spain.
Sole
Carme
C
Pascual
Marta
M
Moubarak
Rana S
RS
Perez-Garcia
M Jose
MJ
Gozzelino
Raffaella
R
Iglesias
Victoria
V
Badiola
Nahuai
N
Bayascas
Jose R
JR
Llecha
Nuria
N
Rodriguez-Alvarez
Jose
J
Soriano
Eduardo
E
Yuste
Victor J
VJ
Comella
Joan X
JX
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016716:PC12 Cells; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051381:Rats; D053218:Receptors, Death Domain / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; C421307:FAIM protein, human; D051034:Inhibitor of Apoptosis Proteins; D020033:Protein Isoforms; D053218:Receptors, Death Domain