FAIM

Official Full Name

Fas apoptotic inhibitory molecule

Organism

Homo sapiens

GeneID

55179

Background

The protein encoded by this gene protects against death receptor-triggered apoptosis and regulates B-cell signaling and differentiation. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

Synonyms

FAIM1;

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Detailed Information

Faim is a 1.2-kb gene that encodes a Fas apoptosis inhibitory molecule (FAIM). The encoded protein protects against death receptor-triggered apoptosis and regulates B-cell signaling and differentiation. Faim is broadly expressed in various tissues and its sequence is highly conserved evolutionarily, suggesting that its role extends beyond lymphocyte homeostasis. Several transcript variants encoding different isoforms have been found for this gene. 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. Diseases associated with FAIM include Milker's Nodule and Contagious Pustular Dermatitis. Among its related pathways are apoptosis, autophagy and neurotrophic factor-mediated Trk receptor signaling.

Faim and Fas Resistant

FAIM was characterized as an inhibitor of Fas that was upregulated in B-cells resistant to Fas-mediated cell death, and whose overexpression in primary B cells is coordinately regulated with sIg signals that block Fas killing. Furthermore, the influence of FAIM appears to be specific to Fas-induced cell death, according to Thomas J. Schneider’s research. FAS is a member of the TNF-receptor superfamily which contains a death domain. The interaction of FAS with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The Fas/Fas ligand (FasL) system is one of an expanding family of receptor–ligand pairs involved in cell fate determination in a variety of cell types, notably including those of lymphoid origin. Fas engagement initiates an intracellular signaling cascade through FADD-mediated caspase 8. It also triggers mitochondrial cytochrome c release which involved in apoptosis pathway, and activates caspase 9 and downstream caspases.

Death Receptors and Nervous System

There is growing evidence that Death receptors (DRs, such as Fas or tumor necrosis factor R1) play non-apoptotic roles that are fundamental for the development of the nervous system. DRs and their ligands are expressed in the nervous system, particularly during development. DR activity can be regulated or blocked by anti-apoptotic proteins such as c-FLIP (FLICE-inhibitory protein), C-IAP-1/2 (cellular inhibitor of apoptosis-1/2), or the anti-apoptotic members of the Bcl-2 family. Other DR-regulatory molecules, such as Lifeguard (LFG) or PEA-15 (phosphoprotein enriched in astrocytes-15 kDa), also present in the nervous system. Signaling pathways, including nuclear factor κB (NF-κB) or the extracellular-regulated kinase (ERK), controlling neuronal death and survival are crucial for the normal development and function of the nervous system. Later reported, FAIM was identified as an endogenous antagonist regulating DR-mediated neuronal cell death.

Faim Figure 1 Schematic representation of FAIM family proteins in the apoptotic death receptor (DR) signaling cascade. (Laura Planells-Ferrer, et al. 2016)

FAIM_S and FAIM_L

There are two forms of Fas Apoptotic Inhibitory Molecules. The former one is FAIM_S, widely expressed in the nervous system, and first identified as a Fas antagonist in B-cells. The later one is FAIM_L, a cytosolic soluble protein, and an alternative spliced form containing 22 aa longer at the N terminus. It is almost exclusively expressed in the nervous system. During neuronal differentiation, FAIM_L is upregulated in expression level. FAIM_L and FAIM_S play different roles in the nervous system. FAIM_L is an endogenous antagonist of death receptors, and prevents death receptor-induced apoptosis at the level of or upstream caspase-8 activation. While FAIM_S promotes neuronal differentiation but it is not an anti-apoptotic molecule in this system, increasing the neurite outgrowth induced by neurotrophins and interfering with nuclear factor κB pathway activation. FAIM_L, but not FAIM_S, interacts with Fas, and its binding can be displaced by FADD. FAIM_L could be responsible for maintaining initiator caspases inactive, like caspase-8, after receptor engagement protecting neurons from the cytotoxic action of death ligands.

References:

Nagata S, Golstein P. The Fas death factor. Science. 1995; 267:1449-1456.
Park C, Sakamaki K, Tachibana O, Yamashima T, Yamashita J, Yonehara S Expression of fas antigen in the normal mouse brain. Biochem Biophys Res Commun. 1998; 252:623–628.
Liston P, Young SS, Mackenzie AE, Korneluk RG (1997) Life and death decisions: the role of the IAPs in modulating programmed cell death. Apoptosis. 2:423-441.
Miguel F. Segura, et al. The Long Form of Fas Apoptotic Inhibitory Molecule Is Expressed Specifically in Neurons and Protects Them against Death Receptor-Triggered Apoptosis. Journal of Neuroscience. 2007, 27 (42) 11228-11241.
Thomas J. Schneider, et al. A Novel Gene Coding for a Fas Apoptosis Inhibitory Molecule (FAIM) Isolated from Inducibly Fas-resistant B Lymphocytes. J EXP Med. 1999; 189(6): 949-956.
Laura Planells-Ferrer, et al. Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system. J. Neurochem. 2016; 139,11-21.

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