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-FLIPL 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-FLIPL 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-FLIPL positively regulates autophagy, by enhancing Beclin-1 protein stability.

Tomaipitinca, L., Petrungaro, S., D'Acunzo, P., Facchiano, A., Dubey, A., Rizza, S., et al. (2021). c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability. CELL DEATH & DISEASE, 12(7), 686 [10.1038/s41419-021-03957-5].

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

D'Acunzo, Pasquale;Rizza, Salvatore;Cecconi, Francesco;
2021

Abstract

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-FLIPL 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-FLIPL 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-FLIPL positively regulates autophagy, by enhancing Beclin-1 protein stability.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/06
English
Animals
Beclin-1
CASP8 and FADD-Like Apoptosis Regulating Protein
Fibroblasts
HEK293 Cells
Humans
Mice
Molecular Docking Simulation
Nedd4 Ubiquitin Protein Ligases
Proteasome Endopeptidase Complex
Protein Binding
Protein Stability
Ubiquitination
Autophagy
Tomaipitinca, L., Petrungaro, S., D'Acunzo, P., Facchiano, A., Dubey, A., Rizza, S., et al. (2021). c-FLIP regulates autophagy by interacting with Beclin-1 and influencing its stability. CELL DEATH & DISEASE, 12(7), 686 [10.1038/s41419-021-03957-5].
Tomaipitinca, L; Petrungaro, S; D'Acunzo, P; Facchiano, A; Dubey, A; Rizza, S; Giulitti, F; Gaudio, E; Filippini, A; Ziparo, E; Cecconi, F; Giampietri, C
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/303787
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