Abstract
In response to nutrient deprivation, the cell mobilizes an extensive amount of membrane to form and grow the autophagosome, allowing the progression of autophagy. By providing membranes and stimulating LC3 lipidation, COPII (Coat Protein Complex II) promotes autophagosome biogenesis. Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting SEC23B degradation. Phosphorylated and stabilized SEC23B associates with SEC24A and SEC24B, but not SEC24C and SEC24D, and they re-localize to the ER-Golgi intermediate compartment, promoting autophagic flux. We propose that, in the presence of nutrients, FBXW5 limits COPII-mediated autophagosome biogenesis. Inhibition of this event by ULK1 ensures efficient execution of the autophagic cascade in response to nutrient starvation.
Highlights
Macro-autophagy is a highly conserved process present in all eukaryotes, which allows the degradation of proteins and organelles by lysosomes (Hurley and Young, 2017; Klionsky et al, 2016; Lamb et al, 2013)
Either co-expression with dominant negative (DN)-CUL1 or addition of MLN4924 blocked the FBXW5-dependent degradation of SEC23B (Figure 1C and Figure 1F)
We demonstrated that FBXW5 targets SEC23B for degradation to limit autophagy during basal, unperturbed conditions
Summary
Macro-autophagy (more commonly referred to as autophagy) is a highly conserved process present in all eukaryotes, which allows the degradation of proteins and organelles by lysosomes (Hurley and Young, 2017; Klionsky et al, 2016; Lamb et al, 2013). It is characterized by the formation of the double-membraned autophagosome that transports cytoplasmic cargos to lysosomes, where the autophagic cargo is subjected to degradation. Due to its role in many cellular processes, it is not surprising that deregulation of autophagy plays a role in many human diseases, such as neurodegenerative disorders, cancer, and infection (Jiang and Mizushima, 2014; Rybstein et al, 2018)
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