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

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 a...

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Bibliographic Details
Published in:Cell death & disease 2021-07, Vol.12 (7), p.686-686, Article 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: Article
Language:English
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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
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-021-03957-5