AMPK regulates ESCRT-dependent microautophagy of proteasomes concomitant with proteasome storage granule assembly during glucose starvation
Open Access
- 18 November 2019
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 15 (11), e1008387
- https://doi.org/10.1371/journal.pgen.1008387
Abstract
The ubiquitin-proteasome system regulates numerous cellular processes and is central to protein homeostasis. In proliferating yeast and many mammalian cells, proteasomes are highly enriched in the nucleus. In carbon-starved yeast, proteasomes migrate to the cytoplasm and collect in proteasome storage granules (PSGs). PSGs dissolve and proteasomes return to the nucleus within minutes of glucose refeeding. The mechanisms by which cells regulate proteasome homeostasis under these conditions remain largely unknown. Here we show that AMP-activated protein kinase (AMPK) together with endosomal sorting complexes required for transport (ESCRTs) drive a glucose starvation-dependent microautophagy pathway that preferentially sorts aberrant proteasomes into the vacuole, thereby biasing accumulation of functional proteasomes in PSGs. The proteasome core particle (CP) and regulatory particle (RP) are regulated differently. Without AMPK, the insoluble protein deposit (IPOD) serves as an alternative site that specifically sequesters CP aggregates. Our findings reveal a novel AMPK-controlled ESCRT-mediated microautophagy mechanism in the regulation of proteasome trafficking and homeostasis under carbon starvation. Protein homeostasis is critical for maintaining organismal health. The cellular dysfunction caused by accumulation and aggregation of aberrant proteins or other normally short-lived proteins is associated with aging and many human diseases, including neurodegenerative disorders, diabetes, and various types of cancer. The eukaryotic ubiquitin-proteasome system regulates numerous cellular processes and through selective protein degradation helps maintain cellular protein homeostasis under normal growth conditions. However, hundreds of cellular granules or condensates are formed during carbon starvation in yeast cells, including proteasome storage granules (PSGs). PSGs result from a massive relocation of proteasomes from the nucleus to the cytoplasm under these conditions. However, how cells regulate proteasome homeostasis under these conditions remains largely unknown. Here, we demonstrate that AMPK (AMP-activated protein kinase), a master cellular energy regulator, drives ESCRT (endosomal sorting complexes required for transport)-dependent microautophagy of aberrant proteasomes. This allows rapid re-mobilization of functional proteasomes from PSGs upon glucose refeeding. Previous studies had identified classical macroautophagy as a means of degrading proteasomes during starvation. Our work shows that direct uptake of proteasomes into the vacuole (lysosome) by microautophagy is a major means of proteasome elimination under limiting glucose conditions.This publication has 66 references indexed in Scilit:
- Formation and dissociation of proteasome storage granules are regulated by cytosolic pHThe Journal of cell biology, 2013
- The AMPK signalling pathway coordinates cell growth, autophagy and metabolismNature, 2011
- Atg8: an autophagy-related ubiquitin-like protein familyGenome Biology, 2011
- Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to MitophagyScience, 2011
- AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1Nature, 2011
- Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulatorMolecular Systems Biology, 2009
- Misfolded proteins partition between two distinct quality control compartmentsNature, 2008
- Reversible cytoplasmic localization of the proteasome in quiescent yeast cellsThe Journal of cell biology, 2008
- Functional profiling of the Saccharomyces cerevisiae genomeNature, 2002
- A TECHNIQUE FOR ULTRACRYOTOMY OF CELL SUSPENSIONS AND TISSUESThe Journal of cell biology, 1973