Rinciple function, protein degradation.40 The vacuole maintains protein homeostasis under physiological conditions by degrading senescent, superfluous, and damaged proteins and organelles. Vacuole function is also vital under conditions of nutrient stress, when cell growth and proliferation are downregulated and proteins must be broken down so that their constituent amino acids can be recycled.41 Impressively, degradation of up to 85 of the cell’s intracellular protein content has been observed during nutrient starvation.42 Nutrient stress is encountered when yeast reach stationary phase, or when they undergo sporulation. Some of the cues known to trigger nutrient stress include carbon and nitrogen starvation, and to a lesser extent when there is a lack of essential amino acids, nucleotides, and sulfates.43,44 This next section summarizes the various degradation functions attributed to the vacuole, and the distinct routes that deliver proteins to this organelle for degradation.Autophagy Autophagy, also known as macroautophagy, is a process whereby bulk cytoplasmic material and organelles are isolated in a double-membrane vesicle known as an autophagosome.45 The autophagosome fuses with the vacuole, where its contents are degraded and the constituent components are recycled. This mechanism is conserved throughout eukaryotes, and is used to maintain cellular homeostasis under physiological conditions by eliminating long-lived proteins and damaged organelles. Autophagy can also be induced under conditions of nutrient stress and during specific stages in the cell cycle, such as in stationary phase or during sporulation.46,47 Autophagy is mediated by over 30 autophagy-related proteins, known as the Atg proteins.48 The Atg proteins act during a series of sequential steps: induction of autophagy, cargo recognition, vesicle nucleation, expansion and completion of the autophagosome, Atg protein recycling, fusion of the autophagosome with the vacuole, vesicle breakdown, and macromolecular recycling. A notable type of selective autophagy is known as the cytoplasm-to-vacuole targeting (Cvt) pathway. In contrast to macroautophagy, the Cvt pathway occurs during nutrient-rich conditions and is a constitutive process.ISRIB 49 The Cvt pathway controls the selective transport of homooligomeric vacuolar proteins. Only three substrates in yeast are known to be targeted to the vacuole by this pathway: aminopeptidase 1 (Ape1),e28023-Cellular Logisticsvolume014 Landes Bioscience. Do not distributeTable 1. Saccharomyces cerevisiae vacuolar proteases. Only those vacuolar resident proteases are shown whose activities and functions have been established experimentally (see text for details) Protease Gene Activity Proteolytically activated by Pep4 and Prb1 Trafficking pathway secretory Function initiator of protease activation cascade; protein degredation protease activation; protease degredation peptide degredation peptide degredation glutathione degredation unknown unknown Known P1 site amino acids Phe, Leu, Tyr, Trp, Thr, Asn, Gln, Glu, Lys, Ala, ile Leu, Arg, Phe, Tyr, Gln, Lys Ala, Gly, val, Leu, ile, Met, PheProteinase APEPaspartyl endoproteaseProteinase B Carboxypeptidase Y Carboxypeptidase S Aminopeptidase i Aminopeptidase Y Dipeptidylaminopeptidase BPRB1 PRC1 CPS1 APE1 APE3 DAPserine endoprotease serine carboxypeptidase Zinc metalloprotease Zinc metalloprotease metalloprotease serine dipeptidasePep4 and Prb1 Pep4 and Prb1 Prb1 Prb1 Prb1 nonesecretory CPY path.Abexinostat PMID:28630660
