Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system

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 FAIM 1, FAIM 2, and FAIM 3 inhibit Fas‐induced cell death, they are not structurally related, nor do they share expression patterns. Moreover, they inhibit apoptosis through completely different mechanisms. FAIM 1 and FAIM 2 protect neurons from DR ‐induced apoptosis and are involved in neurite outgrowth and neuronal plasticity. FAIM 1 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 FAIM 1 levels are found in Alzheimer's disease, thus sensitizing neurons to tumor necrosis factor alpha and prompting neuronal loss. FAIM 2 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 FAIM 2 in diseases of the nervous system, such as ischemia, bacterial meningitis, and neuroblastoma. The less characterized member of the FAIM family is FAIM 3, which is expressed in tissues of the digestive and urinary tracts, bone marrow and testes, and restricted to the cerebellum in the nervous system. FAIM 3 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. FAIM 3 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 FAIM s 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.