ESCRTing proteasomes to the lysosome

Clearance of excess or damaged cellular components is crucial for homeostasis and under stress and defects in this process result in multiple diseases, including neurodegeneration [1]. This clearance is done in two sites: the proteasome, which degrades proteins, and the lysosome, which can degrade all macromolecules and organelles. Proteasomes are multi-protein machines composed of a 20S core particle (CP) capped with two regulatory particles (RP), which direct ubiquitinated proteins to the core cavity, where proteases reside [2]. The lysosome, a membrane-bound organelle with an acidic environment, contains diverse degradative enzymes that function in this milieu. In addition to endocytosis, in which endosomes fuse with lysosomes, two other ways lead into the lysosome: macro-autophagy and micro-autophagy. In macro-autophagy, the double-membrane autophagosome (AP) engulfs cargo and fuses with the lysosome, whereas in micro-autophagy cargo is engulfed by the lysosomal membrane itself. While there is plenty of information about macro-autophagy, not much is known about micro-autophagy [3]. In both cases, the membrane engulfing the cargo needs to seal and the mechanism of this sealing has been a major question in the autophagy field. Another question in the degradation field has been how proteasomes recycle. During normal growth of yeast cells, the majority of the proteasomes reside in the nucleus and damaged proteasomes are shuttled to the lysosome via a selective macro-autophagy pathway, proteaphagy [2]. During stress, proteasomes relocate to the cytoplasm. Under nitrogen starvation, macro-autophagy is vastly induced and excess of cellular components, including proteasomes, are delivered to the lysosome (vacuole in yeast) for degradation. It was recently shown that in nitrogen-starvation induced macro-autophagy, ESCRT complexes play a role in sealing APs to allow their fusion with the lysosome [4]. Under glucose starvation, normal proteasomes are stored in proteasome storage granules (PSGs), which dissolve when glucose is added back [2]. However, it was not clear what happens to aberrant proteasomes under carbon stress (Fig 1). Li et al., address this question [5]. They identified the AMPK and ESCRT complexes (see Table 1) in a genome-wide screen for gene-deletion mutants defective in proteasome degradation during glucose starvation and determined their effect on proteasome fate. Their three major findings are: First, under carbon stress, damaged proteasomes are delivered to the lysosome via micro-autophagy in an AMPKand ESCRT-dependent manner. Second, when AMPK is absent, the CP of proteasomes accumulate in the iPOD, a deposit site for protein aggregates [6]. Third, whereas under nitrogen starvation proteasomes are degraded together with other cellular components, under carbon starvation proteasomes are sorted to different destinations and only damaged proteasomes are degraded (Fig 1). This sorting is an example of a more economical solution of cells to carbon stress than the extensive degradation of cellular components that occurs under nitrogen starvation. The emerging picture puts the lysosome at the top of the cell food chain: While both proteasomes and the lysosome can degrade cellular components, proteasomes get degraded by the PLOS GENETICS