A novel role of c-FLIP protein in regulation of autophagy

The protein c-FLIP, well known as an apoptosis modulator, shows extensive sequence homology with Caspase 8, but is devoid of enzymatic activity. Increasing data underline that c-FLIP has a complex role in cellular homeostasis. The protein can play different roles in the same pathway depending on its expression level and its several isoforms. Although c-FLIP involvement in autophagy has been reported, few and controversial data are available regarding its function within the molecular machinery responsible for autophagic process. This issue has been addressed in the present work. We compared WT MEFs (Mouse Embryonic Fibroblasts) and c-FLIP-/- MEFs treated with autophagy-inducing stimuli and we found that autophagic flux is weaker in c-FLIP-/- MEFs than in WT cells. Therefore, we ran an analysis of specific markers of each autophagic phase. Our data indicate that the absence of c-FLIP does not affect the induction of the process, while the expression levels of factors involved in the nucleation of autophagosomes are compromised in cells that do not express c-FLIP. As c-FLIP is a scaffold protein and it participates to cellular processes binding other proteins and either assembling or destabilizing complexes, we investigated and found a physical interaction between c-FLIP and Beclin-1. Finally, a correlation between c-FLIP absence and Beclin-1 degradation by proteasome emerged.