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Daniel J Klionsky – One of the best experts on this subject based on the ideXlab platform.

  • Psp2, a novel regulator of Autophagy that promotes AutophagyRelated Protein translation
    Cell Research, 2019
    Co-Authors: Aileen Ariosa, Haina Huang, Katrin Karbstein, Daniel J Klionsky

    Abstract:

    MacroAutophagy/Autophagy defines an evolutionarily conserved catabolic process that targets cytoplasmic components for lysosomal degradation. The process of Autophagy from initiation to closure is tightly executed and controlled by the concerted action of AutophagyRelated (Atg) Proteins. Although substantial progress has been made in characterizing transcriptional and post-translational regulation of ATG /Atg genes/Proteins, little is known about the translational control of Autophagy. Here we report that Psp2, an RGG motif Protein, positively regulates Autophagy through promoting the translation of Atg1 and Atg13, two Proteins that are crucial in the initiation of Autophagy. During nitrogen starvation conditions, Psp2 interacts with the 5′ UTR of ATG1 and ATG13 transcripts in an RGG motif-dependent manner and with eIF4E and eIF4G2, components of the translation initiation machinery, to regulate the translation of these transcripts. Deletion of the PSP2 gene leads to a decrease in the synthesis of Atg1 and Atg13, which correlates with reduced Autophagy activity and cell survival. Furthermore, deactivation of the methyltransferase Hmt1 constitutes a molecular switch that regulates Psp2 arginine methylation status as well as its mRNA binding activity in response to starvation. These results reveal a novel mechanism by which Atg Proteins become upregulated to fulfill the increased demands of Autophagy activity as part of translational reprogramming during stress conditions, and help explain how ATG genes bypass the general block in Protein translation that occurs during starvation.

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  • dhh1 promotes Autophagy Related Protein translation during nitrogen starvation
    PLOS Biology, 2019
    Co-Authors: Xu Liu, Zhiyuan Yao, Meiyan Jin, Sim Namkoong, Zhangyuan Yin, Jun Hee Lee, Daniel J Klionsky

    Abstract:

    MacroAutophagy (hereafter Autophagy) is a well-conserved cellular process through which cytoplasmic components are delivered to the vacuole/lysosome for degradation and recycling. Studies have revealed the molecular mechanism of transcriptional regulation of AutophagyRelated (ATG) genes upon nutrient deprivation. However, little is known about their translational regulation. Here, we found that Dhh1, a DExD/H-box RNA helicase, is required for efficient translation of Atg1 and Atg13, two Proteins essential for Autophagy induction. Dhh1 directly associates with ATG1 and ATG13 mRNAs under nitrogen-starvation conditions. The structured regions shortly after the start codons of the two ATG mRNAs are necessary for their translational regulation by Dhh1. Both the RNA-binding ability and helicase activity of Dhh1 are indispensable to promote Atg1 translation and Autophagy. Moreover, eukaryotic translation initiation factor 4E (EIF4E)-associated Protein 1 (Eap1), a target of rapamycin (TOR)-regulated EIF4E binding Protein, physically interacts with Dhh1 after nitrogen starvation and facilitates the translation of Atg1 and Atg13. These results suggest a model for how some ATG genes bypass the general translational suppression that occurs during nitrogen starvation to maintain a proper level of Autophagy.

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  • Look people, “Atg” is an abbreviation for “AutophagyRelated.” That’s it.
    Autophagy, 2012
    Co-Authors: Daniel J Klionsky

    Abstract:

    Prior to the adoption of the unified nomenclature for naming AutophagyRelated genes and Proteins there were at least ten different names being used in fungal systems. Accordingly, in 2003 the majority of the researchers (at that time) working in fungal Autophagy decided it would be advantageous to agree on a single name so that it was no longer necessary to search through the literature (or hope that the authors of the paper you were reading would inform you) to determine that APG1 was the same gene as AUT3, CVT10, GSA10, PAZ1 or PDD7—this gene now has a standard name of ATG1.1 This nomenclature has been adopted in most other eukaryotic systems, further simplifying the naming of these genes and Proteins. As noted in the nomenclature paper, “ATG” and “Atg” stand for “AutophagyRelated” gene or Protein, respectively. That is, “ATG” means “AutophagyRelated,” and that is it. It does not mean “AutophagyRelated gene” or “AutophagyRelated Protein.” The abbreviation derives from just the first word, Autophagy, as in AutophagyRelated.

    It does not make sense for “ATG” to represent “AutophagyRelated gene;” otherwise, when people refer to an “ATG gene” this would translate into “AutophagyRelated gene gene,” which sounds rather absurd. Similarly, “Atg” does not represent “AutophagyRelated Protein” when referring to a Protein, for obvious reasons; otherwise, the “Atg1 Protein” would be spelled out as “AutophagyRelated Protein 1 Protein,” which seems a little redundant. So, “ATG” and “Atg” are simply abbreviations for “AutophagyRelated.” If you want to say “AutophagyRelated gene” or “AutophagyRelated Protein,” you can use “ATG gene” or “Atg Protein.” Note that I am not going to cite incorrect examples of the use of these abbreviations because there are far too many. Also, I am using the capitalization that applies to yeast in these examples. If I was referring to humans the abbreviations would be “ATG” and “ATG” for the gene and Protein, respectively, or “Atg” and “ATG” for the mouse system.2

    That said, while we are on the subject of names, “Cvt” is an abbreviation for “cytoplasm to vacuole targeting” (or “cytoplasm-to-vacuole targeting,” with dashes).3 “Cvt” does not stand for “cytoplasm-to-vacuole,”4,5 which ignores the letter “t.” It also does not stand for “cytosol-to-vacuole-targeting,”6 “cytoplasm to vacuole (cvt) trafficking,”7 or “cytoplasm-to-vacuole transport.”8 In a similar vein, the abbreviation “TAKA” when used to refer to the TAKA assay is an abbreviation for “transport of Atg9 after knocking out ATG1.”9 “TAKA” does not stand for “take Atg1 kinase away,”4 or any other permutations you might be able to come up with.

    A final note about nomenclature concerns the Atg12 conjugation complex. Both Atg12 and Atg8 are unusual in that they become covalently attached to another molecule. Noncovalent interactions are typically indicated with a standard dash “-” as in “Atg1-Atg13.” To denote the covalent attachment we use an en dash “–” as in “Atg8–PE” as opposed to “Atg8-PE”. Now, going back to the Atg12 complex, Atg16 binds Atg5 directly, not Atg12. Thus, it makes sense to write this as “Atg5-Atg16” using a standard dash. One could write “Atg16-Atg5,” but in general we list the lower number first unless we are trying to indicate something specific about the interactions (as with “Atg17-Atg31-Atg29” because Atg29 appears to interact with Atg31 directly, and not with Atg17). So, where is “Atg12” added to this interaction? If we agree on the order “Atg5-Atg16,” there is only once choice, and that is “Atg12–Atg5-Atg16” because Atg12 is covalently attached to Atg5 (note the use of the en dash between these two Proteins) and not Atg16. Therefore, please use the correct designations of “Atg12–Atg5” and “Atg12–Atg5-Atg16” and not “Atg5-Atg12,”10-17 “Atg5/Atg12,”18 “ATG5/ATG12,”19 “Atg5-Atg12/Atg16,”20 “Atg5-Atg12/Atg16L1,”21 “ATG16/ATG5/ATG12”19 or “Atg5-Atg12-Atg16”15 (I am citing some arbitrary examples where the incorrect nomenclature was used, but I could list many more).

    Thus, if you want to use these abbreviations correctly, consider the definitions as explained here. Alternatively, take a look at “A comprehensive glossary of AutophagyRelated molecules and processes”22 (the second edition).

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Fuyuhiko Inagaki – One of the best experts on this subject based on the ideXlab platform.

  • structure of the novel c terminal domain of vacuolar Protein sorting 30 Autophagy Related Protein 6 and its specific role in Autophagy
    Journal of Biological Chemistry, 2012
    Co-Authors: Nobuo N. Noda, Yoshinori Ohsumi, Takafumi Kobayashi, Wakana Adachi, Yuko Fujioka, Fuyuhiko Inagaki

    Abstract:

    Vacuolar Protein sorting 30 (Vps30)/AutophagyRelated Protein 6 (Atg6) is a common component of two distinct phosphatidylinositol 3-kinase complexes. In complex I, Atg14 links Vps30 to Vps34 lipid kinase and exerts its specific role in Autophagy, whereas in complex II, Vps38 links Vps30 to Vps34 and plays a crucial role in vacuolar Protein sorting. However, the molecular role of Vps30 in each pathway remains unclear. Here, we report the crystal structure of the carboxyl-terminal domain of Vps30. The structure is a novel globular fold comprised of three β-sheet-α-helix repeats. Truncation analyses showed that the domain is dispensable for the construction of both complexes, but is specifically required for Autophagy through the targeting of complex I to the pre-autophagosomal structure. Thus, the domain is named the β-α repeated, Autophagy-specific (BARA) domain. On the other hand, the N-terminal region of Vps30 was shown to be specifically required for vacuolar Protein sorting. These structural and functional investigations of Vps30 domains, which are also conserved in the mammalian ortholog, Beclin 1, will form the basis for studying the molecular functions of this Protein family in various biological processes.

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  • STRUCTURE OF THE NOVEL C-TERMINAL DOMAIN OF VACUOLAR Protein SORTING 30/AutophagyRelated Protein 6 AND ITS SPECIFIC ROLE IN Autophagy
    Journal of Biological Chemistry, 2012
    Co-Authors: Nobuo N. Noda, Yoshinori Ohsumi, Takafumi Kobayashi, Wakana Adachi, Yuko Fujioka, Fuyuhiko Inagaki

    Abstract:

    Vacuolar Protein sorting 30 (Vps30)/AutophagyRelated Protein 6 (Atg6) is a common component of two distinct phosphatidylinositol 3-kinase complexes. In complex I, Atg14 links Vps30 to Vps34 lipid kinase and exerts its specific role in Autophagy, whereas in complex II, Vps38 links Vps30 to Vps34 and plays a crucial role in vacuolar Protein sorting. However, the molecular role of Vps30 in each pathway remains unclear. Here, we report the crystal structure of the carboxyl-terminal domain of Vps30. The structure is a novel globular fold comprised of three β-sheet-α-helix repeats. Truncation analyses showed that the domain is dispensable for the construction of both complexes, but is specifically required for Autophagy through the targeting of complex I to the pre-autophagosomal structure. Thus, the domain is named the β-α repeated, Autophagy-specific (BARA) domain. On the other hand, the N-terminal region of Vps30 was shown to be specifically required for vacuolar Protein sorting. These structural and functional investigations of Vps30 domains, which are also conserved in the mammalian ortholog, Beclin 1, will form the basis for studying the molecular functions of this Protein family in various biological processes.

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  • AutophagyRelated Protein 32 acts as autophagic degron and directly initiates mitophagy.
    Journal of Biological Chemistry, 2012
    Co-Authors: Noriko Kondo-okamoto, Nobuo N. Noda, Sho Suzuki, Hitoshi Nakatogawa, Ikuko Takahashi, Miou Matsunami, Ayako Hashimoto, Fuyuhiko Inagaki, Yoshinori Ohsumi, Koji Okamoto

    Abstract:

    AutophagyRelated degradation selective for mitochondria (mitophagy) is an evolutionarily conserved process that is thought to be critical for mitochondrial quality and quantity control. In budding yeast, AutophagyRelated Protein 32 (Atg32) is inserted into the outer membrane of mitochondria with its N- and C-terminal domains exposed to the cytosol and mitochondrial intermembrane space, respectively, and plays an essential role in mitophagy. Atg32 interacts with Atg8, a ubiquitin-like Protein localized to the autophagosome, and Atg11, a scaffold Protein required for selective AutophagyRelated pathways, although the significance of these interactions remains elusive. In addition, whether Atg32 is the sole Protein necessary and sufficient for initiation of autophagosome formation has not been addressed. Here we show that the Atg32 IMS domain is dispensable for mitophagy. Notably, when anchored to peroxisomes, the Atg32 cytosol domain promoted Autophagy-dependent peroxisome degradation, suggesting that Atg32 contains a module compatible for other organelle Autophagy. X-ray crystallography reveals that the Atg32 Atg8 family-interacting motif peptide binds Atg8 in a conserved manner. Mutations in this binding interface impair association of Atg32 with the free form of Atg8 and mitophagy. Moreover, Atg32 variants, which do not stably interact with Atg11, are strongly defective in mitochondrial degradation. Finally, we demonstrate that Atg32 forms a complex with Atg8 and Atg11 prior to and independent of isolation membrane generation and subsequent autophagosome formation. Taken together, our data implicate Atg32 as a bipartite platform recruiting Atg8 and Atg11 to the mitochondrial surface and forming an initiator complex crucial for mitophagy.

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Nobuo N. Noda – One of the best experts on this subject based on the ideXlab platform.

  • the Autophagy Related Protein kinase atg1 interacts with the ubiquitin like Protein atg8 via the atg8 family interacting motif to facilitate autophagosome formation
    Journal of Biological Chemistry, 2012
    Co-Authors: Hitoshi Nakatogawa, Nobuo N. Noda, Sho Suzuki, Shiran Ohbayashi, Machiko Sakohnakatogawa, Soichiro Kakuta, Hiromi Kirisako, Chika Kondokakuta, Hayashi Yamamoto, Yoshinori Ohsumi

    Abstract:

    In Autophagy, a cup-shaped membrane called the isolation membrane is formed, expanded, and sealed to complete a double membrane-bound vesicle called the autophagosome that encapsulates cellular constituents to be transported to and degraded in the lysosome/vacuole. The formation of the autophagosome requires AutophagyRelated (Atg) Proteins. Atg8 is a ubiquitin-like Protein that localizes to the isolation membrane; a subpopulation of this Protein remains inside the autophagosome and is transported to the lysosome/vacuole. In the budding yeast Saccharomyces cerevisiae, Atg1 is a serine/threonine kinase that functions in the initial step of autophagosome formation and is also efficiently transported to the vacuole via Autophagy. Here, we explore the mechanism and significance of this autophagic transport of Atg1. In selective types of Autophagy, receptor Proteins recognize degradation targets and also interact with Atg8, via the Atg8 family interacting motif (AIM), to link the targets to the isolation membrane. We find that Atg1 contains an AIM and directly interacts with Atg8. Mutations in the AIM disrupt this interaction and abolish vacuolar transport of Atg1. These results suggest that Atg1 associates with the isolation membrane by binding to Atg8, resulting in its incorporation into the autophagosome. We also show that mutations in the Atg1 AIM cause a significant defect in Autophagy, without affecting the functions of Atg1 implicated in triggering autophagosome formation. We propose that in addition to its essential function in the initial stage, Atg1 also associates with the isolation membrane to promote its maturation into the autophagosome.

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  • structure of the novel c terminal domain of vacuolar Protein sorting 30 Autophagy Related Protein 6 and its specific role in Autophagy
    Journal of Biological Chemistry, 2012
    Co-Authors: Nobuo N. Noda, Yoshinori Ohsumi, Takafumi Kobayashi, Wakana Adachi, Yuko Fujioka, Fuyuhiko Inagaki

    Abstract:

    Vacuolar Protein sorting 30 (Vps30)/AutophagyRelated Protein 6 (Atg6) is a common component of two distinct phosphatidylinositol 3-kinase complexes. In complex I, Atg14 links Vps30 to Vps34 lipid kinase and exerts its specific role in Autophagy, whereas in complex II, Vps38 links Vps30 to Vps34 and plays a crucial role in vacuolar Protein sorting. However, the molecular role of Vps30 in each pathway remains unclear. Here, we report the crystal structure of the carboxyl-terminal domain of Vps30. The structure is a novel globular fold comprised of three β-sheet-α-helix repeats. Truncation analyses showed that the domain is dispensable for the construction of both complexes, but is specifically required for Autophagy through the targeting of complex I to the pre-autophagosomal structure. Thus, the domain is named the β-α repeated, Autophagy-specific (BARA) domain. On the other hand, the N-terminal region of Vps30 was shown to be specifically required for vacuolar Protein sorting. These structural and functional investigations of Vps30 domains, which are also conserved in the mammalian ortholog, Beclin 1, will form the basis for studying the molecular functions of this Protein family in various biological processes.

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  • STRUCTURE OF THE NOVEL C-TERMINAL DOMAIN OF VACUOLAR Protein SORTING 30/AutophagyRelated Protein 6 AND ITS SPECIFIC ROLE IN Autophagy
    Journal of Biological Chemistry, 2012
    Co-Authors: Nobuo N. Noda, Yoshinori Ohsumi, Takafumi Kobayashi, Wakana Adachi, Yuko Fujioka, Fuyuhiko Inagaki

    Abstract:

    Vacuolar Protein sorting 30 (Vps30)/AutophagyRelated Protein 6 (Atg6) is a common component of two distinct phosphatidylinositol 3-kinase complexes. In complex I, Atg14 links Vps30 to Vps34 lipid kinase and exerts its specific role in Autophagy, whereas in complex II, Vps38 links Vps30 to Vps34 and plays a crucial role in vacuolar Protein sorting. However, the molecular role of Vps30 in each pathway remains unclear. Here, we report the crystal structure of the carboxyl-terminal domain of Vps30. The structure is a novel globular fold comprised of three β-sheet-α-helix repeats. Truncation analyses showed that the domain is dispensable for the construction of both complexes, but is specifically required for Autophagy through the targeting of complex I to the pre-autophagosomal structure. Thus, the domain is named the β-α repeated, Autophagy-specific (BARA) domain. On the other hand, the N-terminal region of Vps30 was shown to be specifically required for vacuolar Protein sorting. These structural and functional investigations of Vps30 domains, which are also conserved in the mammalian ortholog, Beclin 1, will form the basis for studying the molecular functions of this Protein family in various biological processes.

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