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Identification and characterization of new isoforms of human fas apoptotic inhibitory molecule (FAIM)
Elena Coccia1,2,3, Isabel Calleja-Yagüe1,2,3, Laura Planells-Ferrer1,2,3
1Cell Signaling and Apoptosis Group, Vall d´Hebron Institute of Research (VHIR), Barcelona, Spain.
Abstract:
Fas Apoptosis Inhibitory Molecule (FAIM) is an evolutionarily highly conserved death receptor antagonist, widely expressed and known to participate in physiological and pathological processes. Two FAIM transcript variants have been characterized to date, namely FAIM short (FAIM-S) and FAIM long (FAIM-L). FAIM-S is ubiquitously expressed and serves as an anti-apoptotic protein in the immune system. Furthermore, in neurons, this isoform promotes NGF-induced neurite outgrowth through NF-кB and ERK signaling. In contrast FAIM-L is found only in neurons, where it exerts anti-apoptotic activity against several stimuli. In addition to these two variants, in silico studies point to the existence of two additional isoforms, neither of which have been characterized to date. In this regard, here we confirm the presence of these two additional FAIM isoforms in human fetal brain, fetal and adult testes, and placenta tissues. We named them FAIM-S_2a and FAIM-L_2a since they have the same sequence as FAIM-S and FAIM-L, but include exon 2a. PCR and western blot revealed that FAIM-S_2a shows ubiquitous expression in all the tissues and cellular models tested, while FAIM-L_2a is expressed exclusively in tissues of the nervous system. In addition, we found that, when overexpressed in non-neuronal cells, the splicing factor nSR100 induces the expression of the neuronal isoforms, thus identifying it as responsible for the generation of FAIM-L and FAIM-L_2a. Functionally, FAIM-S_2a and FAIM-L_2a increased neurite outgrowth in response to NGF stimulation in a neuronal model. This observation thus, supports the notion that these two isoforms are involved in neuronal differentiation. Furthermore, subcellular fractionation experiments revealed that, in contrast to FAIM-S and FAIM-L, FAIM-S_2a and FAIM-L_2a are able to localize to the nucleus, where they may have additional functions. In summary, here we report on two novel FAIM isoforms that may have relevant roles in the physiology and pathology of the nervous system.
Insights
Two new Fas Apoptosis Inhibitory Molecule (FAIM) isoforms, FAIM-S_2a and FAIM-L_2a, were identified. These novel isoforms, particularly FAIM-L_2a, are crucial for neuronal differentiation and may play roles in nervous system disorders.
Area of Science:
- Molecular Biology
- Neuroscience
- Cell Biology
Background:
- Fas Apoptosis Inhibitory Molecule (FAIM) is a highly conserved antagonist of death receptors involved in various biological processes.
- Two FAIM transcript variants, FAIM-S and FAIM-L, are known, with distinct expression patterns and functions.
- FAIM-S is broadly expressed and anti-apoptotic, promoting neurite outgrowth in neurons.
- FAIM-L is neuron-specific and provides anti-apoptotic activity.
Purpose of the Study:
- To confirm the existence and characterize two additional, previously unconfirmed FAIM isoforms suggested by in silico studies.
- To investigate the expression patterns and functional roles of these novel FAIM isoforms, particularly in the nervous system.
- To identify the regulatory mechanisms, such as splicing factors, involved in the generation of neuronal FAIM isoforms.
Main Methods:
- Polymerase Chain Reaction (PCR) and Western blot analysis to detect and confirm the expression of novel FAIM isoforms.
- Tissue analysis of human fetal brain, testes, and placenta to determine expression localization.
- Overexpression studies in non-neuronal cells to identify regulatory splicing factors.
- Neuronal cell models to assess the functional impact of novel FAIM isoforms on neurite outgrowth.
- Subcellular fractionation to determine the localization of FAIM isoforms within cells.
Main Results:
- Two novel FAIM isoforms, FAIM-S_2a and FAIM-L_2a, incorporating exon 2a, were confirmed in human tissues including fetal brain, testes, and placenta.
- FAIM-S_2a exhibited ubiquitous expression, while FAIM-L_2a was exclusively detected in nervous system tissues.
- The splicing factor nSR100 was identified as responsible for inducing neuronal FAIM isoform expression when overexpressed.
- Both FAIM-S_2a and FAIM-L_2a enhanced NGF-stimulated neurite outgrowth in a neuronal model, suggesting roles in neuronal differentiation.
- Unlike previously known isoforms, FAIM-S_2a and FAIM-L_2a were found to localize within the cell nucleus.
Conclusions:
- Two novel FAIM isoforms, FAIM-S_2a and FAIM-L_2a, have been identified and characterized.
- FAIM-L_2a is a neuron-specific isoform, and both new isoforms contribute to neuronal differentiation.
- The splicing factor nSR100 plays a key role in generating neuronal FAIM isoforms.
- The nuclear localization of FAIM-S_2a and FAIM-L_2a suggests additional, yet to be discovered, nuclear functions.
- These findings highlight potential roles for novel FAIM isoforms in nervous system physiology and pathology.
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