Abstract
Apoptosis plays an important role during development, control of tissue homeostasis and in pathological contexts. Apoptosis is executed mainly through the intrinsic pathway or the death receptor pathway, i.e., extrinsic pathway. These processes are tightly controlled by positive and negative regulators that dictate pro- or anti-apoptotic death receptor signaling. One of these regulators is the Fas Apoptotic Inhibitory Molecule (FAIM). This death receptor antagonist has two main isoforms, FAIM-S (short) which is the ubiquitously expressed, and a longer isoform, FAIM-L (long), which is mainly expressed in the nervous system. Despite its role as a death receptor antagonist, FAIM also participates in cell death-independent processes such as nerve growth factor-induced neuritogenesis or synaptic transmission. Moreover, FAIM isoforms have been implicated in blocking the formation of protein aggregates under stress conditions or de-regulated in certain pathologies such as Alzheimer’s and Parkinson’s diseases. Despite the role of FAIM in physiological and pathological processes, little is known about the molecular mechanisms involved in the regulation of its expression. Here, we seek to investigate the post-transcriptional regulation of FAIM isoforms by microRNAs (miRNAs). We found that miR-206, miR-1-3p, and miR-133b are direct regulators of FAIM expression. These findings provide new insights into the regulation of FAIM and may provide new opportunities for therapeutic intervention in diseases in which the expression of FAIM is altered.
Highlights
Several types of molecules are able to block apoptotic pathways, conferring cells with protection against threatening stimuli
In order to screen for potential miRNAs able to modulate the expression of Fas Apoptotic Inhibitory Molecule (FAIM), we compared the prediction of putative miRNA-binding sites in the 3 UTR of FAIM from five different prediction algorithms, i.e., TargetScan, miRanda, miRWalk, miRMap, and miRDB
Death receptor-induced cell death is essential during development due to its role regulating tissue homeostasis and differentiation
Summary
Several types of molecules are able to block apoptotic pathways, conferring cells with protection against threatening stimuli. The extrinsic apoptotic pathway is mediated by death receptors that integrate and transmit the extracellular apoptotic stimuli. In the last 20 years, mounting evidence has shed light on the physiological and pathological functions of these molecules and has widened the array of identified responses elicited by these receptors beyond cell death. Fas receptor and TNF receptors (TNFRs) are paradigmatic cases of receptors that can Regulation of FAIM by miRNAs trigger apoptotic and non-apoptotic responses depending on the cellular and molecular context (Marques-Fernandez et al, 2013). It was later found to play multifaceted roles in other physiological processes such as the protective or deleterious effects of TNFα in neurodegenerative disorders (Carriba et al, 2015), regulating axon-selective pruning, hippocampal long-term depression (LTD) (MartinezMarmol et al, 2016) and opposition to stress-induced accumulation of protein aggregates (Kaku and Rothstein, 2020)
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