FAIM2

Official Full Name

Fas apoptotic inhibitory molecule 2

Organism

Homo sapiens

GeneID

23017

Background

Predicted to enable calcium channel activity. Involved in regulation of neuron apoptotic process. Acts upstream of or within negative regulation of extrinsic apoptotic signaling pathway via death domain receptors. Located in Golgi membrane and membrane raft. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

LFG; LFG2; NGP35; NMP35; TMBIM2;

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Detailed Information

Human FAIM2 gene is located in the q13.12 zone of chromosome, first found in Somia's research for the Fas signaling transmission inhibition molecules in the human lung fibroblast cell line MRC-5, a protein isolated to be anti-apoptotic in cells exposed into FasL while not TNFα. Immunofluorescence and immunoprecipitation assay confirmed that FAIM2 is membrane-related and interacts with Fas receptor directly. Homology search revealed this protein was human homolog of mice's NMP35 protein, firstly founded in the PCR experiment for the identification of regulation genes in the rat sciatic nerve development. Human FAIM2 gene is cDNA coded for 35kDa protein possessed a neuronal expression model mainly expressed in adult central nervous system. While NMP35 seems to be localized in somas, dendrites, and post-synaptic membranes, involved in the adult central nervous system synapse biology. The anti-apoptotic effect in the neuron system of FAIM2 was firstly confirmed by FAIM2 silencing induced granular neuron's caspase-8 splitting and apoptosis sensitization in Fas exposure. The expression of FAIM 2 in neuron is dependent on phosphatidylinositol 3-kinase-Akt pathway, which plays a pivotal role in cellular system. The hidden mechanism of FAIM 2 's blockage on Fas induced apoptosis is further confirmed to be preferentially co-localized and interact with Fas receptor.

Faim-2 Act as Death-receptor Antagonists in The Nervous System

There are many FAIM2 homologues in different species due to the biological evolution conservation. Amino acid sequence analysis revealed that FAIM2 is a muti-transmembrane protein with 7 transmembrane structure zone and shared common structures with TMBIM protein family members. BI-1, also known as TMBIM6, proven to be cell-protective in DNA damage and ER stress induced apoptosis, is localized in ER to regulate the calcium signing transmission by the interaction with anti-apoptosis protein Bcl-Xl. A recent study reported FAIM2 regulates Fas-stimulated calcium concentration elevation by the interaction with FAIM2 in ER, and the more intriguing is cut down of calcium release stimulated by Fas is somewhat dependent on the expression of FAIM2, even though it can be anti-apoptotic by inhibiting mitochondria permeabilization. In view of inositol-1,4,5, -triphosphate receptors' mediator role of calcium releasing from inner storage through the indirect influence on the interaction between Bcl-2 and Bcl-Xl, or another explanation to the FAIM2s anti-apoptosis effect maybe itself a calcium release channel. In conclusion, more and more evidence shows that the protective effect of FAIM2 in Fas induced apoptosis is calcium signaling related but more research is needed to reveal the exact mechanism.

Another Role of Faim-2 in Nervous System

In addition to the involvement in the apoptosis, more and more new studies have revealed that neuronal differentiation, axonal growth, and neuroplasticity are also related with FAIM2. The loss of FAIM2 in the early stage after birth would minimize cerebellar volume and deter the development of Purkinje cells, thus reducing cell density and presenting abnormal morphology according to Mendoza's research. Localization and translation of FAIM2 mRNA in different compartments in cultured adult dorsal root ganglion neurons promoted axonal growth.

Fig 1. Schematic representation of FAIM family proteins in the apoptotic death receptor signaling cascade (Yuan et al. 2018)

References:

Laura Planells-Ferrer, Jorge Urresti. (2016) 'Fas apoptosis inhibitory molecules: more than death-receptor antagonists in the nervous system, Journal of Neurochemistry, doi: 10.1111/jnc.13729.
Fernandez M. Segura M. F. Sole C. (2007) 'Lifeguard/neuronal membrane protein 35 regulates Fas ligand-mediated apoptosis in neurons via micro domain recruitment, J. Neurochem, 103, 190–203.
Beier C. P. Wischhusen J. Gleichmann M. (2005) 'FasL (CD95L/ APO-1L) resistance of neurons mediated by phosphatidylinositol 3-kinase-Akt/protein kinase B-dependent expression of lifeguard/ neuronal membrane protein 35. J. Neurosci. 25, 6765–6774.

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