SUMMARY PARAGRAPH for VPS30
Autophagy is a highly conserved eukaryotic pathway for sequestering and transporting bulk cytoplasm, including proteins and organelle material, to the lysosome for degradation (reviewed in 9). Upon starvation for nutrients such as carbon, nitrogen, sulfur, and various amino acids, or upon endoplasmic reticulum stress, cells initiate formation of a double-membrane vesicle, termed an autophagosome, that mediates this process (10, 11, reviewed in 12). Approximately 30 autophagy-related (Atg) proteins have been identified in S. cerevisiae, 17 of which are essential for formation of the autophagosome (reviewed in 13). Null mutations in most of these genes prevent induction of autophagy, and cells do not survive nutrient starvation; however, these mutants are viable in rich medium. Some of the Atg proteins are also involved in a constitutive biosynthetic process termed the cytoplasm-to-vacuole targeting (Cvt) pathway, which uses autophagosomal-like vesicles for selective transport of hydrolases aminopeptidase I (Lap4p) and alpha-mannosidase (Ams1p) to the vacuole (14, 15).
Autophagy proceeds via a multistep pathway (a summary diagram (download pdf) kindly provided by Dan Klionsky). First, nutrient availability is sensed by the TORC1 complex and also cooperatively by protein kinase A and Sch9p (16, 17). Second, signals generated by the sensors are transmitted to the autophagosome-generating machinery comprised of the 17 Atg gene products. These 17 proteins collectively form the pre-autophagosomal structure/phagophore assembly site (PAS). The PAS generates an isolation membrane (IM), which expands and eventually fuses along the edges to complete autophagosome formation. At the vacuole the outer membrane of the autophagosome fuses with the vacuolar membrane and autophagic bodies are released, disintegrated, and their contents degraded for reuse in biosynthesis (18 and reviewed in 13).
about the Cytoplasm-to-vacuole targeting (Cvt) pathway
Cytoplasm-to-vacuole targeting (Cvt) is a constitutive and specific form of autophagy that uses autophagosomal-like vesicles for selective transport of hydrolases aminopeptidase I (Lap4p) and alpha-mannosidase (Ams1p) to the vacuole (14, 15). Unlike autophagy, which is primarily a catabolic process, Cvt is a biosynthetic process. Like autophagosomes, Cvt vesicles form at a structure known as the phagophore assembly site (PAS) (also called the pre-autophagosomal structure). The PAS structure generates an isolation membrane (IM), which expands and eventually fuses along the edges to complete vesicle formation. At the vacuole, the outer membrane of the Cvt vesicle fuses with the vacuolar membrane, the vesicle is degraded, and the cargos are released and processed into their mature forms by vacuolar peptidases (reviewed in 19). The Cvt pathway has not been observed outside of yeast, and enzymes specifically involved in this pathway are not well conserved in other organisms (20 and references therein).
Vps30p is a subunit of two distinct phosphatidylinositol (PtdIns) 3-kinase complexes: Complex I, which is involved in autophagy, and Complex II, which functions in vacuolar protein sorting (6). Both complexes contain Vps30p, the PtdIns 3-kinase Vps34p, and Vps15p, a regulatory kinase that tethers the complexes to membranes and activates Vps34p activity. Additionally, each complex contains one unique subunit which acts as a connector between Vps30p and the rest of the complex: Atg14p in Complex I and Vps38p in Complex II (21 and references therein, and reviewed in 22).
Vps30p localizes to vacuolar membranes, endosomes, and the PAS. Vps30p localization to endosomes is dependent on Vps38p while PAS localization is Atg14p-dependent (21). Vps30p is itself required for proper localization of Atg8p and the Atg5p-Atg12p.Atg16p complex to the PAS (23). Mutations in vps30 lead to lower PtdIns 3-phosphate levels, sensitivity to chemicals that induce the unfolded protein response, and defects in autophagy, vacuolar targeting of carboxypeptidase Y (Prc1p), ER-associated protein degradation (ERAD), and retrograde transport from the endosome to the Golgi (5, 24, 7, 25, 26).
VPS30 is highly conserved, and homologs have been identified in organisms such as soil amoeba (atg6), Arabidopsis (atg6), worm (bec-1), mouse (beclin-1), and human (BECN1) (27 and reviewed in 22). In other organisms, Vps30p orthologs have been shown to be involved in the processes of autophagy, development, life-span regulation, apoptosis, and tumor suppression (reviewed in 22).
about autophagy nomenclature
The initial identification of factors involved in autophagy was carried out by several independent labs, which led to a proliferation of nomenclature for the genes and gene products involved. The differing gene name acronyms from these groups included APG, AUT, CVT, GSA, PAG, PAZ, and PDD (4 and references therein). A concerted effort was made in 2003 by the scientists working in the field to unify the nomenclature for these genes, and "AuTophaGy-related" genes are now denoted by the letters ATG (4). In addition to the ATG gene names that have been assigned to S. cerevisiae proteins and their orthologs, several ATG gene names, including ATG25, ATG28, and ATG30, have been used to designate proteins in other ascomycete yeast species for which there is no identifiable equivalent in S. cerevisiae (20, 28).
Last updated: 2008-02-08