TY - JOUR
T1 - The ULK1-FBXW5-SEC23B nexus controls autophagy
AU - Jeong, Yeon Tae
AU - Simoneschi, Daniele
AU - Keegan, Sarah
AU - Melville, David
AU - Adler, Natalia S.
AU - Saraf, Anita
AU - Florens, Laurence
AU - Washburn, Michael P.
AU - Cavasotto, Claudio N.
AU - Fenyö, David
AU - Cuervo, Ana Maria
AU - Rossi, Mario
AU - Pagano, Michele
N1 - Funding Information:
The authors thank A. D. Matteis and R. Schekman for reagents; J. Pagan for critical reading the manuscript. M.P. and YT.J. are grateful to T.M. Thor and S.O. Hong, respectively, for continuous support. This work was funded by grants from the National Institute of Health (R01-CA076584 and R01-GM057587) to M.P., and Agencia Nacional de Promoción Científica y Tecnológica-Argentina (PICT-2014-0458, PICT2016-2620) to M.R, and (PICT-2014-3599) to C.N.C. C.N.C. thanks the National System of High-Performance Computing (Sistemas Nacionales de Computación de Alto Rendimiento, SNCAD) and the Computational Centre of High-Performance Computing (Centro de Computación de Alto Rendimiento, CeCAR) for granting use of their computational resources. M.P. is an Investigator with the Howard Hughes Medical Institute.
Publisher Copyright:
© 2018, eLife Sciences Publications Ltd. All rights reserved.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.42253
DO - 10.7554/eLife.42253
M3 - Article
C2 - 30596474
AN - SCOPUS:85060601762
SN - 2050-084X
VL - 7
JO - eLife
JF - eLife
M1 - e42253
ER -