c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability

• Published in: Cell death & disease Vol. 12; no. 7; p. 686
• Main Authors: Tomaipitinca, Luana, Petrungaro, Simonetta, D’Acunzo, Pasquale, Facchiano, Angelo, Dubey, Amit, Rizza, Salvatore, Giulitti, Federico, Gaudio, Eugenio, Filippini, Antonio, Ziparo, Elio, Cecconi, Francesco, Giampietri, Claudia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08-07-2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 14/63; 631/45; 631/80/39; 82; 82/80; 96/109; 96/44; 96/95; Antibodies; Apoptosis; Autophagy; Biochemistry; Bioinformatics; Biomedical and Life Sciences; c-FLIP protein; Cell Biology; Cell Culture; Embryo fibroblasts; FLIP protein; Immunology; Life Sciences; Moesin; Phagocytosis; Phagosomes; Proteasomes; Proteins; Ubiquitination
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03957-5

c-FLIP (cellular FLICE-like inhibitory protein) protein is mostly known as an apoptosis modulator. However, increasing data underline that c-FLIP plays multiple roles in cellular homoeostasis, influencing differently the same pathways depending on its expression level and isoform predominance. Few and controversial data are available regarding c-FLIP function in autophagy. Here we show that autophagic flux is less effective in
c-FLIP−/−
than in WT MEFs (mouse embryonic fibroblasts). Indeed, we show that the absence of c-FLIP compromises the expression levels of pivotal factors in the generation of autophagosomes. In line with the role of c-FLIP as a scaffold protein, we found that c-FLIP
L
interacts with Beclin-1 (
BECN1
: coiled-coil, moesin-like BCL2-interacting protein), which is required for autophagosome nucleation. By a combination of bioinformatics tools and biochemistry assays, we demonstrate that c-FLIP
L
interaction with Beclin-1 is important to prevent Beclin-1 ubiquitination and degradation through the proteasomal pathway. Taken together, our data describe a novel molecular mechanism through which c-FLIP
L
positively regulates autophagy, by enhancing Beclin-1 protein stability.