Abstract
26S proteasome abundance is tightly regulated at multiple levels, including the elimination of excess or inactive particles by autophagy. In yeast, this proteaphagy occurs upon nitrogen starvation but not carbon starvation, which instead stimulates the rapid sequestration of proteasomes into cytoplasmic puncta termed proteasome storage granules (PSGs). Here, we show that PSGs help protect proteasomes from autophagic degradation. Both the core protease and regulatory particle sub-complexes are sequestered separately into PSGs via pathways dependent on the accessory proteins Blm10 and Spg5, respectively. Modulating PSG formation, either by perturbing cellular energy status or pH, or by genetically eliminating factors required for granule assembly, not only influences the rate of proteasome degradation, but also impacts cell viability upon recovery from carbon starvation. PSG formation and concomitant protection against proteaphagy also occurs in Arabidopsis, suggesting that PSGs represent an evolutionarily conserved cache of proteasomes that can be rapidly re-mobilized based on energy availability.
Highlights
Protein homeostasis is an essential process by which cells attempt to maintain proteome integrity by regulating protein synthesis, folding, transport and degradation
Given the critical roles for the ubiquitin-26S proteasome system (UPS) and autophagy in cell regulation, maintaining amino acid supply, and mitigating the toxic effects of aggregation-prone proteins, it is unsurprising that these pathways are highly regulated (Collins and Goldberg, 2017; Dikic, 2017)
We further investigated starvation-induced proteaphagy in yeast and Arabidopsis and surprisingly found that, while proteasomes are rapidly eliminated during nitrogen starvation, they remain stable in response to carbon starvation, even though bulk autophagy is up-regulated
Summary
Protein homeostasis (proteostasis) is an essential process by which cells attempt to maintain proteome integrity by regulating protein synthesis, folding, transport and degradation. UPS substrates are first tagged with a poly-ubiquitin chain using a highly polymorphic E1-E2-E3 enzymatic cascade, which facilitates their recognition and degradation by the 26S proteasome (Finley et al, 2012). This 2.5-MDa proteolytic machine is composed of two functionally distinct sub-complexes; the 20S core protease (CP) and the 19S regulatory particle (RP; Lander et al, 2012; Bhattacharyya et al, 2014). The CP houses the peptidase active sites responsible for cleaving substrates into short peptides, whereas the RP contains activities for substrate recognition, deubiquitylation, unfolding, and translocation into the CP lumen (Collins and Goldberg, 2017; Dikic, 2017)
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