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

Cell Death Dis. 2021 Jul 8;12(7):686. doi: 10.1038/s41419-021-03957-5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Beclin-1 / metabolism*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • HEK293 Cells
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Nedd4 Ubiquitin Protein Ligases / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Stability
  • Ubiquitination

Substances

  • Beclin-1
  • Becn1 protein, mouse
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cflar protein, mouse
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, mouse
  • Proteasome Endopeptidase Complex