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.
Highlights
The ubiquitin-proteasome system (UPS) is a conserved proteolytic system responsible for the highly selective degradation of cellular proteins
Protein homeostasis is critical for maintaining organismal health
The cellular dysfunction caused by accumulation and aggregation of aberrant proteins or other normally shortlived proteins is associated with aging and many human diseases, including neurodegenerative disorders, diabetes, and various types of cancer
Summary
The ubiquitin-proteasome system (UPS) is a conserved proteolytic system responsible for the highly selective degradation of cellular proteins. Conjugation of ubiquitin to substrates targets them to the proteasome for degradation [1, 2]. The 26S proteasome comprises a 20S core particle (CP) with a 19S regulatory particle (RP) on one or both ends of the CP [1]. In the CP, four stacked rings are assembled from different β-subunits (β1-β7) and α-subunits (α1-α7). The RP is assembled from two multisubunit subcomplexes termed the base and lid [1]. The RP is responsible for substrate binding, deubiquitylation, unfolding, and translocation [1, 3,4,5]
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