Two Distinct Vps34 Phosphatidylinositol 3–Kinase Complexes Function in Autophagy and Carboxypeptidase Y Sorting inSaccharomyces cerevisiae

By A. Kihara, Takeshi Noda, Naotada Ishihara, Y. Ohsumi. Journal of Cell Biology, 2001

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Vps30p/Apg6p is required for both autophagy and sorting of carboxypeptidase Y (CPY). Although Vps30p is known to interact with Apg14p, its precise role remains unclear. We found that two proteins copurify with Vps30p. They were identified by mass spectrometry to be Vps38p and Vps34p, a phosphatidylinositol (PtdIns) 3–kinase. Vps34p, Vps38p, Apg14p, and Vps15p, an activator of Vps34p, were coimmunoprecipitated with Vps30p. These results indicate that Vps30p functions as a subunit of a Vps34 PtdIns 3–kinase complex(es). Phenotypic analyses indicated that Apg14p and Vps38p are each required for autophagy and CPY sorting, respectively, whereas Vps30p, Vps34p, and Vps15p are required for both processes. Coimmunoprecipitation using anti-Apg14p and anti-Vps38p antibodies and pull-down experiments showed that two distinct Vps34 PtdIns 3–kinase complexes exist: one, containing Vps15p, Vps30p, and Apg14p, functions in autophagy and the other containing Vps15p, Vps30p, and Vps38p functions in CPY sorting. The vps34 and vps15 mutants displayed additional phenotypes such as defects in transport of proteinase A and proteinase B, implying the existence of another PtdIns 3–kinase complex(es). We propose that multiple Vps34p–Vps15p complexes associated with specific regulatory proteins might fulfill their membrane trafficking events at different sites.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c18bd91630a735613e3543a26d3615a0fe6485f6

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Citations in the corpus

Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. (2007, background): “The VPS34 complex described above functions in the promotion of autophagy, as a membrane-associated complex (Kihara et al., 2001; Stein et al., 2003).”
Molecular definitions of autophagy and related processes (2017, positive): “Either mammalian phagophores or omegasomes, or both, stain positively for ULK1, ATG13, ATG101, FIP200, VPS34, BECN1, VPS15, ATG5, ATG12, ATG16L1, DFCP1 as well as for lipidated LC3 family members (Antonioli et al , 2016).”
Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. (2003, positive): “The yeast homolog Apg6/Vps30p is also involved in vacuolar protein sorting (53, 54), raising the possibility that mammalian Beclin 1, as part of a PI3K complex that may localize in the trans-Golgi network (20), is involved in other membrane-trafficking pathways.”
Hierarchy of Atg proteins in pre‐autophagosomal structure organization (2007, background): “I, together with Vps30p/Atg6p ( Kihara et al. 2001 ).”
Autophagy and autophagy-related proteins in cancer (2020, background): “The ATG14L (Atg14) can associate with and anchor the PI3KC3-CI to the PAS [103–106] and the Vps38 can localize the PI3KC3-CII to vacuolar and endosomal membranes [103, 107].”
Potential therapeutic applications of autophagy (2007, background): “Class I PtdIns-3-kinases control the activation of the kinases AKT1 and mammalian target of rapamycin ( mTOR ), and are inhibitory for autophag”
Beclin–phosphatidylinositol 3‐kinase complex functions at the trans‐Golgi network (2001, background): “…vol. 2 | no. 4 | 2001 lysosomal enzyme transport (Brown et al., 1995; Davidson, 1995), it is likely that Beclin–PtdIns 3-kinase complex functions in such transport as well as autophagy, in a manner analogous to the yeast complex (Herman and Emr, 1990; Kametaka et al., 1998; Kihara et al., 2001).”
Autophagy: process and function. (2007, background): “In contrast, it is known in yeast that Atg6/Vps30 functions in both autophagy and the Vps pathways by forming two distinct class III PI3-kinase complexes (Kihara et al. 2001).”