Fas apoptotic inhibitory molecule 2: a novel regulator of autophagy by facilitating autophagosome-lysosome fusion

Abstract

In the adult brain, programmed cell death (PCD) is a critical process to maintain an adequate pool of self-renewing neural stem cells (NSCs) and newly generated cells in the brain. To date, the studies of key players regulating PCD have been extensively centered around apoptosis. Therefore, I sought to expand the knowledge on underlying mechanisms of autophagic cell death. Based on the gene expression profiling of the model of autophagic cell death in NSCs, I discovered Fas apoptotic inhibitory molecule 2 (FAIM2) as one of the marker genes. FAIM2 is a seven-transmembrane domain-containing protein that plays a neuroprotective role via antagonizing the extrinsic apoptosis signaling. However, whether FAIM2 plays a role in other forms of molecular signaling has been unknown. Here I show that FAIM2 localizes to the lysosomes at basal state and facilitates autophagy through interaction with LC3 in human neuroblastoma SH-SY5Y cells. FAIM2 overexpression increased autophagy flux, while autophagy flux was impaired in shRNAmediated knockdown (shFAIM2) cells, and the impairment was more evident in the presence of rapamycin. In shFAIM2 cells, autophagosome maturation through fusion with lysosomes was impaired, leading to accumulation of autophagosomes. A functional LC3- interacting region motif within FAIM2 was essential for the interaction with LC3 and the rescue of autophagy flux in shFAIM2 cells, while LC3-binding property of FAIM2 was dispensable for the anti-apoptotic function in response to Fas receptor-mediated apoptosis. Suppression of autophagosome maturation was also observed in a null mutant of Caenorhabditis elegans lacking xbx-6, the ortholog of FAIM2. Current study suggests that FAIM2 is a novel regulator of autophagy mediating autophagosome maturation through the interaction with LC3.