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Elife. 2018 Dec 31;7. pii: e42253. doi: 10.7554/eLife.42253.

The ULK1-FBXW5-SEC23B nexus controls autophagy.

Author information

1
Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, United States.
2
Perlmutter NYU Cancer Center, NYU School of Medicine, New York, United States.
3
Institute for System Genetics, NYU School of Medicine, New York, United States.
4
Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
5
Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
6
Translational Medicine Research Institute (IIMT), CONICET, Facultad de Ciencias Biomédicas and Facultad deIngeniería, Universidad Austral, Pilar-Derqui, Argentina.
7
The Stowers Institute for Medical Research, Kansas, United States.
8
Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas, United States.
9
Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, United States.
10
Howard Hughes Medical Institute, New York University School of Medicine, New York, United States.

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.

KEYWORDS:

CRLs; SCF; ULK1; autophagy; cancer; cell; cell biology; human; ubiquitin

PMID:
30596474
PMCID:
PMC6351106
DOI:
10.7554/eLife.42253
[Indexed for MEDLINE]
Free PMC Article

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