Proteasome storage granules protect proteasomes from autophagic degradation upon carbon starvation

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.

eLife digest

Proteins perform many jobs within an organism, including providing structure and support, and protecting against infection. The levels of the many proteins in a cell need to be carefully controlled so that the correct amounts are present at the right place and time to perform these tasks. This control can be achieved by balancing the production of new proteins with the break down (or degradation) of proteins that are no longer required or become dysfunctional.

Most cells have two pathways for degrading proteins. One pathway breaks down individual proteins specifically marked for elimination; this causes them to be recognized by a structure called the proteasome, which chops proteins into smaller pieces. Larger protein assemblies – including the proteasome itself – are to big for the proteasome and thus need to be degraded by another pathway called autophagy. This process engulfs and delivers parts of a cell to a membrane-bound compartment called the vacuole, which ‘digests’ and recycles these larger constituents.

Proteasomes are degraded by autophagy when they are not working correctly and when nitrogen (a crucial nutrient) is in short supply. However, proteasomes are not degraded when cells lack carbon, even though this starvation is known to activate autophagy in the same way that an absence of nitrogen does. So how do proteasomes escape degradation when cells are starved for carbon?

Marshall and Vierstra now show that upon carbon starvation, proteasomes rapidly exit the cell nucleus and cluster together in the main part of the cell (termed the cytosol). These clusters are known as proteasome storage granules (PSGs). In fungi and plants, mutations or conditions inside the cell that make it difficult for PSGs to assemble cause proteasomes to instead be broken down in the vacuole when carbon availability is low. Clustering into PSGs therefore protects proteasomes from autophagy. This clustering appears advantageous to cells; yeast cells that could form PSGs were better able to start growing again when their nutrient supply improved.

Protein clustering (also known as aggregation) is an important strategy that cells use to survive stressful conditions. However, it can also be harmful when proteins aggregate inappropriately, such as occurs in Alzheimer’s disease. Researchers may be able to use PSG assembly as a convenient model to study the causes and consequences of protein aggregation; this knowledge could ultimately be applied to improve human health and crop productivity.