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Nitrogen Starvation and Rapamycin both Induce Autophagic Degradation of Proteasome Complexes

Under conditions of nitrogen starvation yeast cells need to degrade proteins to obtain nutrients that can be dedicated to the synthesis of proteins involved in crucial cellular processes. Two systems in the cell are responsible for the degradation of most cellular proteins, the ubiquitin‐proteasome system and the lysosome/vacuole, and thus could contribute to this process. The proteasome is a 2.5 MDa complex that consists of a core particle (CP) that harbors the proteolytic active sites within a cylindrical structure, and one or two regulatory particles (RPs), that control substrate binding, unfolding, and entry of substrates into the CP. We reported recently that proteasomes themselves are degraded upon prolonged nitrogen starvation. Using GFP‐tagged proteasome subunits we showed proteasomes are targeted to the vacuole and that this depends on the core autophagy machinery. This degradation, however, does not simply reflect general bulk autophagy of cytosolic proteasomes, because we observed that nuclear proteasomes are exported out of the nucleus upon nitrogen starvation. Furthermore, starvation induces a dissociation of proteasomes into CP and RP. Both subcomplexes are targeted to the vacuole, but depend on different factors; only CP autophagy required the deubiquitinating enzyme Ubp3. Ubp3 is not required for bulk autophagy, further confirming the model that proteasomes are specifically targeted to the vacuole. The next goal of our lab is to understand the signaling pathways and mechanisms that are responsible for the nuclear export and vacuolar targeting of proteasomes. One major signaling pathway inhibited upon nitrogen starvation is the target of rapamycin complex 1 (TORC1) pathway. Surprisingly, it was recently reported by Rousseau and Bertolotti (Nature, 2016) that an inhibitor of this pathway, rapamycin, actually induces an upregulation of proteasomes. Similar to their data, we observe an initial upregulation of proteasome levels and activity upon rapamycin treatment. However, prolonged exposure results in vacuolar targeting and degradation of proteasomes similar to what we reported upon nitrogen starvation. We observed several differences between nitrogen starvation and rapamycin treatment, indicating the autophagic degradation of proteasomes upon nitrogen starvation does not solely depend on the mTORC1 pathway.