ATG18/YFR021W Summary Help

Standard Name ATG18 1
Systematic Name YFR021W
Alias NMR1 2 , CVT18 3 , AUT10 4 , SVP1 5
Feature Type ORF, Verified
Description Phosphoinositide binding protein; required for vesicle formation in autophagy and the cytoplasm-to-vacuole targeting (Cvt) pathway; binds both phosphatidylinositol (3,5)-bisphosphate and phosphatidylinositol 3-phosphate; WD-40 repeat protein; relocalizes from vacuole to cytoplasm upon DNA replication stress; has 4 mammalian homologs WIPI1, WIPI2, WIPI3 and WIPI4/WDR45; mutations in human WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood (4, 5, 6, 7, 8 and see Summary Paragraph)
Name Description AuTophaGy related 1
Chromosomal Location
ChrVI:194812 to 196314 | ORF Map | GBrowse
Gbrowse
Gene Ontology Annotations All ATG18 GO evidence and references
  View Computational GO annotations for ATG18
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
High-throughput
Regulators 3 genes
Resources
Classical genetics
null
overexpression
reduction of function
Large-scale survey
null
overexpression
Resources
89 total interaction(s) for 64 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 13
  • Affinity Capture-RNA: 1
  • Affinity Capture-Western: 6
  • Biochemical Activity: 6
  • Co-localization: 2
  • Co-purification: 1
  • PCA: 2
  • Two-hybrid: 17

Genetic Interactions
  • Negative Genetic: 14
  • Phenotypic Enhancement: 2
  • Phenotypic Suppression: 2
  • Positive Genetic: 16
  • Synthetic Growth Defect: 4
  • Synthetic Lethality: 3

Resources
Expression Summary
histogram
Resources
Length (a.a.) 500
Molecular Weight (Da) 55,102
Isoelectric Point (pI) 5.28
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrVI:194812 to 196314 | ORF Map | GBrowse
SGD ORF map
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..1503 194812..196314 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000001917
SUMMARY PARAGRAPH for ATG18

about autophagy...

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).

about ATG18

ATG18 and ATG21 are paralogous genes that, along with HSV2, encode members of a vacuolar/perivacuolar family of phosphoinositide binding proteins (21, 3, 5, 22). Atg18p is essential for vesicle formation in both autophagy and the Cvt pathway (5, 4). Atg21p is only required for vesicle formation in the Cvt pathway (23) but may have some role in autophagic fidelity (24). Atg18p and Atg21p are WD-40 repeat proteins, expected to fold as seven bladed β-propellers, that are able to bind both phosphatidylinositol (3,5)-bisphosphate (PtdIns(3,5)P2) and phosphatidylinositol 3-phosphate (PtdIns3P) (5, 22).

Atg18p localizes to both the preautophagosomal structure (PAS) and to punctate structures at the vacuolar membrane (6, 3, 4). Localization to these two structures may involve a mechanism that depends on differential phosphatidylinositide binding: PtdIns3P to the PAS and PtdIns(3,5)P2 to the vacuolar membrane (22, 5). Vacuolar localization of Atg18p is also dependent on the transmembrane protein Vac7p (25). PAS-localized Atg18p is involved in localization of the autophagy proteins Atg2p and Atg9p (3, 6). Vacuolar Atg18p is required for retrograde trafficking from the vacuole to the late endosome (5) as well as regulating the activity of the phosphatidylinositol(3)-phosphate 5-kinase Fab1p which affects PtdIns(3,5)P2 levels and vacuolar morphology (25).

atg18 null strains have enlarged vacuoles and high levels of PtdIns(3,5)P2; they are unable to sporulate and unable to grow on media containing glycerol as the sole carbon source (5, 4, 21). Atg18p and Atg21p have also been shown to interact with the transcriptional activator Rtg3p and null atg18 or atg21 mutations result in the reduced expression of RTG-regulated genes (21).

WD-repeat proteins are conserved from yeast to man, and ATG18 homologs have been identified in organisms such as Drosophila (CG11975) and human (WDR45L/WIPI3) (26, 5). Aberrant expression of human WIPI genes has been found in various cancerous tissues (5).

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 (1 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 (1). 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, 27).

Last updated: 2008-02-08 Contact SGD

References cited on this page View Complete Literature Guide for ATG18
1) Klionsky DJ, et al.  (2003) A unified nomenclature for yeast autophagy-related genes. Dev Cell 5(4):539-45
2) Rabitsch KP, et al.  (2001) A screen for genes required for meiosis and spore formation based on whole-genome expression. Curr Biol 11(13):1001-9
3) Guan J, et al.  (2001) Cvt18/Gsa12 is required for cytoplasm-to-vacuole transport, pexophagy, and autophagy in Saccharomyces cerevisiae and Pichia pastoris. Mol Biol Cell 12(12):3821-38
4) Barth H, et al.  (2001) Autophagy and the cytoplasm to vacuole targeting pathway both require Aut10p. FEBS Lett 508(1):23-8
5) Dove SK, et al.  (2004) Svp1p defines a family of phosphatidylinositol 3,5-bisphosphate effectors. EMBO J 23(9):1922-33
6) Reggiori F, et al.  (2004) The Atg1-Atg13 complex regulates Atg9 and Atg23 retrieval transport from the pre-autophagosomal structure. Dev Cell 6(1):79-90
7) Tkach JM, et al.  (2012) Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress. Nat Cell Biol 14(9):966-76
8) Saitsu H, et al.  (2013) De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet 45(4):445-9, 449e1
9) Budovskaya YV, et al.  (2004) The Ras/cAMP-dependent protein kinase signaling pathway regulates an early step of the autophagy process in Saccharomyces cerevisiae. J Biol Chem 279(20):20663-71
10) Takeshige K, et al.  (1992) Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol 119(2):301-11
11) Matsuura A, et al.  (1997) Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene 192(2):245-50
12) Yorimitsu T and Klionsky DJ  (2007) Endoplasmic reticulum stress: a new pathway to induce autophagy. Autophagy 3(2):160-2
13) Suzuki K and Ohsumi Y  (2007) Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae. FEBS Lett 581(11):2156-61
14) Harding TM, et al.  (1996) Genetic and phenotypic overlap between autophagy and the cytoplasm to vacuole protein targeting pathway. J Biol Chem 271(30):17621-4
15) Yorimitsu T and Klionsky DJ  (2005) Atg11 links cargo to the vesicle-forming machinery in the cytoplasm to vacuole targeting pathway. Mol Biol Cell 16(4):1593-605
16) Yorimitsu T, et al.  (2007) Protein Kinase A and Sch9 Cooperatively Regulate Induction of Autophagy in Saccharomyces cerevisiae. Mol Biol Cell 18(10):4180-9
17) Noda T and Ohsumi Y  (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273(7):3963-6
18) Suzuki K, et al.  (2001) The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J 20(21):5971-81
19) Kim J and Klionsky DJ  (2000) Autophagy, cytoplasm-to-vacuole targeting pathway, and pexophagy in yeast and mammalian cells. Annu Rev Biochem 69:303-42
20) Meijer WH, et al.  (2007) ATG genes involved in non-selective autophagy are conserved from yeast to man, but the selective Cvt and pexophagy pathways also require organism-specific genes. Autophagy 3(2):106-16
21) Georgakopoulos T, et al.  (2001) Functional analysis of the Saccharomyces cerevisiae YFR021w/YGR223c/YPL100w ORF family suggests relations to mitochondrial/peroxisomal functions and amino acid signalling pathways. Yeast 18(12):1155-71
22) Stromhaug PE, et al.  (2004) Atg21 is a phosphoinositide binding protein required for efficient lipidation and localization of Atg8 during uptake of aminopeptidase I by selective autophagy. Mol Biol Cell 15(8):3553-66
23) Barth H, et al.  (2002) Mai1p is essential for maturation of proaminopeptidase I but not for autophagy. FEBS Lett 512(1-3):173-9
24) Meiling-Wesse K, et al.  (2004) Atg21 is required for effective recruitment of Atg8 to the preautophagosomal structure during the Cvt pathway. J Biol Chem 279(36):37741-50
25) Efe JA, et al.  (2007) Atg18 Regulates Organelle Morphology and Fab1 Kinase Activity Independent of Its Membrane Recruitment by Phosphatidylinositol 3,5-Bisphosphate. Mol Biol Cell 18(11):4232-4244
26) Proikas-Cezanne T, et al.  (2004) WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Oncogene 23(58):9314-25
27) Farre JC, et al.  (2008) PpAtg30 tags peroxisomes for turnover by selective autophagy. Dev Cell 14(3):365-76