The long form of fas apoptotic inhibitory molecule is expressed specifically in neurons and protects them against death receptor-triggered apoptosis

Abstract

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 (FAIMS ) was first identified as a Fas antagonist in B-cells. Soon after, a longer alternative spliced isoform with unknown function was identified and named FAIML. FAIMS 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 FAIML 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 FAIMS , FAIML does not increase the neurite outgrowth induced by neurotrophins and does not interfere with nuclear factor ĸB pathway activation as FAIMS does. Cells overexpressing FAIML 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 endogenousFAIML protects primary neurons from DR-induced cell death. The detailed analysis of this antagonism shows thatFAIML can bind to Fas receptor and prevent the activation of the initiator caspase-8 induced by Fas. In conclusion, our results indicate that FAIML could be responsible for maintaining initiator caspases inactive after receptor engagement protecting neurons from the cytotoxic action of death ligands.

This work was supported by Spanish Government “Ministerio de Sanidad y Consumo” (contract number PI020051, PI04/2364, Redes Temáticas de Investigación Cooperativa, and CiberNed), Fundació La Caixa (Ayudas a la Investigación en Enfermedades Neurodegenerativas 02/055-00), Ministerio de Educacio´n y Ciencia (SAF-2005- 0176), and Generalitat de Catalunya (Suport als Grups de Recerca Consolidats and Distinció a Joves Investigadors). M.F.S., C.S., and M.J.P.-G. were supported by a postgraduate fellowship from the Spanish Government, Ministerio de Educación y Ciencia and Fondo de Investigación Sanitaria, respectively. R.G. holds a postgraduate fellowship from the Department d’Universitat, Recerca i Societat de la Informació (Generalitat de Catalunya) and Fons Social Europeu. N.B. is the recipient of a postgraduate fellowship from the Gobierno Vasco. V.J.Y. was under a Beatriu de Pino´s contract from Generalitat de Catalunya.