Developmental Cell
Volume 45, Issue 2, 23 April 2018, Pages 245-261.e6
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Article
GRASP55 Senses Glucose Deprivation through O-GlcNAcylation to Promote Autophagosome-Lysosome Fusion

https://doi.org/10.1016/j.devcel.2018.03.023Get rights and content
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Highlights

  • GRASP55 is O-GlcNAcylated under growth condition

  • Upon glucose starvation GRASP55 is de-O-GlcNAcylated and targeted to autophagosomes

  • GRASP55 interacts with LC3-II on autophagosomes and LAMP2 on lysosomes

  • GRASP55 bridges LC3-II and LAMP2 to facilitate autophagosome-lysosome fusion

Summary

The Golgi apparatus is the central hub for protein trafficking and glycosylation in the secretory pathway. However, how the Golgi responds to glucose deprivation is so far unknown. Here, we report that GRASP55, the Golgi stacking protein located in medial- and trans-Golgi cisternae, is O-GlcNAcylated by the O-GlcNAc transferase OGT under growth conditions. Glucose deprivation reduces GRASP55 O-GlcNAcylation. De-O-GlcNAcylated GRASP55 forms puncta outside of the Golgi area, which co-localize with autophagosomes and late endosomes/lysosomes. GRASP55 depletion reduces autophagic flux and results in autophagosome accumulation, while expression of an O-GlcNAcylation-deficient mutant of GRASP55 accelerates autophagic flux. Biochemically, GRASP55 interacts with LC3-II on the autophagosomes and LAMP2 on late endosomes/lysosomes and functions as a bridge between LC3-II and LAMP2 for autophagosome and lysosome fusion; this function is negatively regulated by GRASP55 O-GlcNAcylation. Therefore, GRASP55 senses glucose levels through O-GlcNAcylation and acts as a tether to facilitate autophagosome maturation.

Keywords

GRASP55
LC3
LAMP2
O-GlcNAcylation
glucose starvation
tethering
autophagosome-lysosome fusion
Golgi
Golgi stacking proteins
autophagy

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