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WIPI-Mediated Autophagy and Longevity.

Grimmel M, Backhaus C, Proikas-Cezanne T - Cells (2015)

Bottom Line: WIPI proteins detect this pool of newly produced PI3P and function as essential PI3P effector proteins that recruit downstream autophagy-related (ATG) proteins.Adult lifespan is significantly reduced in ATG-18 mutant animals, demonstrating that longevity as such is crucially determined by essential autophagy factors.As the development of strategies on how to increase health span in humans is increasingly appreciated, we speculate that targeting WIPI protein function might represent a therapeutic opportunity to fight and delay the onset of age-related human diseases.

View Article: PubMed Central - PubMed

Affiliation: Autophagy Laboratory, Department of Molecular Biology, Interfaculty Institute of Cell Biology, Faculty of Science, Eberhard Karls University Tuebingen, Auf der Morgenstelle 15, 72076 Tuebingen, Germany.

ABSTRACT
Autophagy is a lysosomal degradation process for cytoplasmic components, including organelles, membranes, and proteins, and critically secures eukaryotic cellular homeostasis and survival. Moreover, autophagy-related (ATG) genes are considered essential for longevity control in model organisms. Central to the regulatory relationship between autophagy and longevity is the control of insulin/insulin-like growth factor receptor-driven activation of mTOR (mechanistic target of rapamycin), which inhibits WIPI (WD repeat protein interacting with phosphoinositides)-mediated autophagosome formation. Release of the inhibitory mTOR action on autophagy permits the production of PI3P (phosphatidylinositol-3 phosphate), predominantly at the endoplasmic reticulum, to function as an initiation signal for the formation of autophagosomes. WIPI proteins detect this pool of newly produced PI3P and function as essential PI3P effector proteins that recruit downstream autophagy-related (ATG) proteins. The important role of WIPI proteins in autophagy is highlighted by functional knockout of the WIPI homologues ATG-18 and EPG-6 in Caenorhabditis elegans (C. elegans). Adult lifespan is significantly reduced in ATG-18 mutant animals, demonstrating that longevity as such is crucially determined by essential autophagy factors. In this review we summarize the role of WIPI proteins and their C. elegans homologues with regard to the molecular basis of aging. As the development of strategies on how to increase health span in humans is increasingly appreciated, we speculate that targeting WIPI protein function might represent a therapeutic opportunity to fight and delay the onset of age-related human diseases.

No MeSH data available.


Related in: MedlinePlus

The process of WIPI-mediated autophagy. The process of autophagy is initiated by ER-localized production of PI3P leading to the formation of a template membrane, referred to as a phagophore (or isolation membrane) by unknown steps of membrane rearrangements (A). The phagophore elongates by sequestering cytoplasmic cargo, including proteins, lipids, membranes, and organelles, and closes to form a double-membrane vesicle called an autophagosome. Subsequently, the autophagosome delivers the sequestered cargo to the lysosomal compartment for final degradation. During this process the autophagosome fuses with lysosomes to form so-called autolysosomes, where the inner autophagosomal membrane and the cargo are rapidly degraded and the components are released into the cytosol for subsequent recycling or storage purposes. WIPI proteins function as essential PI3P-effector proteins at the nascent autophagosome (B). WIPI proteins specifically bind to PI3P and WIPI2B promotes the conjugation of LC3 to PE (LC3 lipidation) through the recruitment of the ATG12-5/ATG16 complex. LC3 lipidation is initiated by C-terminal cleavage of pro-LC3 by ATG4, which becomes conjugated to PE via ATG7 and ATG3 (C). Conjugation of LC3 to PE, (LC3-PE, also referred to as LC3-II) requires the ATG12-5/ATG16 complex. ATG12-5/ATG16 complex formation is initiated by the conjugation of ATG12 to ATG5 (ATG12-5), via ATG7 and ATG10 (D). Subsequently, ATG16 associates with ATG12-5 to form the multiprotein ATG12-5/ATG16 complex.
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cells-04-00202-f001: The process of WIPI-mediated autophagy. The process of autophagy is initiated by ER-localized production of PI3P leading to the formation of a template membrane, referred to as a phagophore (or isolation membrane) by unknown steps of membrane rearrangements (A). The phagophore elongates by sequestering cytoplasmic cargo, including proteins, lipids, membranes, and organelles, and closes to form a double-membrane vesicle called an autophagosome. Subsequently, the autophagosome delivers the sequestered cargo to the lysosomal compartment for final degradation. During this process the autophagosome fuses with lysosomes to form so-called autolysosomes, where the inner autophagosomal membrane and the cargo are rapidly degraded and the components are released into the cytosol for subsequent recycling or storage purposes. WIPI proteins function as essential PI3P-effector proteins at the nascent autophagosome (B). WIPI proteins specifically bind to PI3P and WIPI2B promotes the conjugation of LC3 to PE (LC3 lipidation) through the recruitment of the ATG12-5/ATG16 complex. LC3 lipidation is initiated by C-terminal cleavage of pro-LC3 by ATG4, which becomes conjugated to PE via ATG7 and ATG3 (C). Conjugation of LC3 to PE, (LC3-PE, also referred to as LC3-II) requires the ATG12-5/ATG16 complex. ATG12-5/ATG16 complex formation is initiated by the conjugation of ATG12 to ATG5 (ATG12-5), via ATG7 and ATG10 (D). Subsequently, ATG16 associates with ATG12-5 to form the multiprotein ATG12-5/ATG16 complex.

Mentions: Autophagosomes, double-membrane vesicles that are formed to sequester and deliver cytoplasmic material for lysosomal degradation, derive from the elongation and closure of a membrane precursor, referred to as an isolation membrane or phagophore (Figure 1A) [5]. The process of autophagy is executed by a set of essential ATG proteins, originally identified in yeast, collectively functioning in precise hierarchies [9] during canonical and non-canonical pathways that control and execute autophagy [10]. During the process of phagophore elongation and autophagosome closure, phosphoinositide 3-kinase class III (PI3KC3) phosphorylates phosphatidylinositol (PI) to generate phosphatidylinositol 3-phosphate (PI3P) [5]. PI3P production represents the initiation signal for autophagosome formation regulated by both canonical and non-canonical autophagy pathways. The four members of the human WIPI protein family (WIPI1-4) are considered to decode the PI3P signal upon specific binding of WIPI proteins to PI3P at the nascent autophagosome (Figure 1B, 2) [11,12]. One of the essential PI3P-effector functions of WIPI2B is the recruitment of the ATG12-5/ATG16 complex that conjugates LC3 to phosphatidylethanolamine (PE) (Figure 1B–D) for subsequent phagophore elongation [13]. Conjugation of LC3 to PE at the phagophore results from the action of two autophagy-specific ubiquitin-like conjugation systems, the LC3 (Figure 1C) and ATG12 (Figure 1D) conjugation system [9]. In order to conjugate LC3 to PE, the C-terminal end of pro-LC3 is cleaved off and exposes a conserved glycine residue used for conjugation to ATG7, followed by the conjugation to ATG3 (Figure 1C). Finally, LC3 is conjugated to PE (LC3 lipidation) and is thereafter referred to as LC3-II (or LC3-PE), the membrane-bound form of LC3 (Figure 1B). LC3 lipidation is executed by a product of the ATG12 conjugation system, the ATG12-5/ATG16 complex (Figure 1D) [9,10,14]. Functionally, membrane-bound LC3 is involved in cargo recognition and hemifusion with incoming membranes to permit phagophore elongation [14,15].


WIPI-Mediated Autophagy and Longevity.

Grimmel M, Backhaus C, Proikas-Cezanne T - Cells (2015)

The process of WIPI-mediated autophagy. The process of autophagy is initiated by ER-localized production of PI3P leading to the formation of a template membrane, referred to as a phagophore (or isolation membrane) by unknown steps of membrane rearrangements (A). The phagophore elongates by sequestering cytoplasmic cargo, including proteins, lipids, membranes, and organelles, and closes to form a double-membrane vesicle called an autophagosome. Subsequently, the autophagosome delivers the sequestered cargo to the lysosomal compartment for final degradation. During this process the autophagosome fuses with lysosomes to form so-called autolysosomes, where the inner autophagosomal membrane and the cargo are rapidly degraded and the components are released into the cytosol for subsequent recycling or storage purposes. WIPI proteins function as essential PI3P-effector proteins at the nascent autophagosome (B). WIPI proteins specifically bind to PI3P and WIPI2B promotes the conjugation of LC3 to PE (LC3 lipidation) through the recruitment of the ATG12-5/ATG16 complex. LC3 lipidation is initiated by C-terminal cleavage of pro-LC3 by ATG4, which becomes conjugated to PE via ATG7 and ATG3 (C). Conjugation of LC3 to PE, (LC3-PE, also referred to as LC3-II) requires the ATG12-5/ATG16 complex. ATG12-5/ATG16 complex formation is initiated by the conjugation of ATG12 to ATG5 (ATG12-5), via ATG7 and ATG10 (D). Subsequently, ATG16 associates with ATG12-5 to form the multiprotein ATG12-5/ATG16 complex.
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Related In: Results  -  Collection

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cells-04-00202-f001: The process of WIPI-mediated autophagy. The process of autophagy is initiated by ER-localized production of PI3P leading to the formation of a template membrane, referred to as a phagophore (or isolation membrane) by unknown steps of membrane rearrangements (A). The phagophore elongates by sequestering cytoplasmic cargo, including proteins, lipids, membranes, and organelles, and closes to form a double-membrane vesicle called an autophagosome. Subsequently, the autophagosome delivers the sequestered cargo to the lysosomal compartment for final degradation. During this process the autophagosome fuses with lysosomes to form so-called autolysosomes, where the inner autophagosomal membrane and the cargo are rapidly degraded and the components are released into the cytosol for subsequent recycling or storage purposes. WIPI proteins function as essential PI3P-effector proteins at the nascent autophagosome (B). WIPI proteins specifically bind to PI3P and WIPI2B promotes the conjugation of LC3 to PE (LC3 lipidation) through the recruitment of the ATG12-5/ATG16 complex. LC3 lipidation is initiated by C-terminal cleavage of pro-LC3 by ATG4, which becomes conjugated to PE via ATG7 and ATG3 (C). Conjugation of LC3 to PE, (LC3-PE, also referred to as LC3-II) requires the ATG12-5/ATG16 complex. ATG12-5/ATG16 complex formation is initiated by the conjugation of ATG12 to ATG5 (ATG12-5), via ATG7 and ATG10 (D). Subsequently, ATG16 associates with ATG12-5 to form the multiprotein ATG12-5/ATG16 complex.
Mentions: Autophagosomes, double-membrane vesicles that are formed to sequester and deliver cytoplasmic material for lysosomal degradation, derive from the elongation and closure of a membrane precursor, referred to as an isolation membrane or phagophore (Figure 1A) [5]. The process of autophagy is executed by a set of essential ATG proteins, originally identified in yeast, collectively functioning in precise hierarchies [9] during canonical and non-canonical pathways that control and execute autophagy [10]. During the process of phagophore elongation and autophagosome closure, phosphoinositide 3-kinase class III (PI3KC3) phosphorylates phosphatidylinositol (PI) to generate phosphatidylinositol 3-phosphate (PI3P) [5]. PI3P production represents the initiation signal for autophagosome formation regulated by both canonical and non-canonical autophagy pathways. The four members of the human WIPI protein family (WIPI1-4) are considered to decode the PI3P signal upon specific binding of WIPI proteins to PI3P at the nascent autophagosome (Figure 1B, 2) [11,12]. One of the essential PI3P-effector functions of WIPI2B is the recruitment of the ATG12-5/ATG16 complex that conjugates LC3 to phosphatidylethanolamine (PE) (Figure 1B–D) for subsequent phagophore elongation [13]. Conjugation of LC3 to PE at the phagophore results from the action of two autophagy-specific ubiquitin-like conjugation systems, the LC3 (Figure 1C) and ATG12 (Figure 1D) conjugation system [9]. In order to conjugate LC3 to PE, the C-terminal end of pro-LC3 is cleaved off and exposes a conserved glycine residue used for conjugation to ATG7, followed by the conjugation to ATG3 (Figure 1C). Finally, LC3 is conjugated to PE (LC3 lipidation) and is thereafter referred to as LC3-II (or LC3-PE), the membrane-bound form of LC3 (Figure 1B). LC3 lipidation is executed by a product of the ATG12 conjugation system, the ATG12-5/ATG16 complex (Figure 1D) [9,10,14]. Functionally, membrane-bound LC3 is involved in cargo recognition and hemifusion with incoming membranes to permit phagophore elongation [14,15].

Bottom Line: WIPI proteins detect this pool of newly produced PI3P and function as essential PI3P effector proteins that recruit downstream autophagy-related (ATG) proteins.Adult lifespan is significantly reduced in ATG-18 mutant animals, demonstrating that longevity as such is crucially determined by essential autophagy factors.As the development of strategies on how to increase health span in humans is increasingly appreciated, we speculate that targeting WIPI protein function might represent a therapeutic opportunity to fight and delay the onset of age-related human diseases.

View Article: PubMed Central - PubMed

Affiliation: Autophagy Laboratory, Department of Molecular Biology, Interfaculty Institute of Cell Biology, Faculty of Science, Eberhard Karls University Tuebingen, Auf der Morgenstelle 15, 72076 Tuebingen, Germany.

ABSTRACT
Autophagy is a lysosomal degradation process for cytoplasmic components, including organelles, membranes, and proteins, and critically secures eukaryotic cellular homeostasis and survival. Moreover, autophagy-related (ATG) genes are considered essential for longevity control in model organisms. Central to the regulatory relationship between autophagy and longevity is the control of insulin/insulin-like growth factor receptor-driven activation of mTOR (mechanistic target of rapamycin), which inhibits WIPI (WD repeat protein interacting with phosphoinositides)-mediated autophagosome formation. Release of the inhibitory mTOR action on autophagy permits the production of PI3P (phosphatidylinositol-3 phosphate), predominantly at the endoplasmic reticulum, to function as an initiation signal for the formation of autophagosomes. WIPI proteins detect this pool of newly produced PI3P and function as essential PI3P effector proteins that recruit downstream autophagy-related (ATG) proteins. The important role of WIPI proteins in autophagy is highlighted by functional knockout of the WIPI homologues ATG-18 and EPG-6 in Caenorhabditis elegans (C. elegans). Adult lifespan is significantly reduced in ATG-18 mutant animals, demonstrating that longevity as such is crucially determined by essential autophagy factors. In this review we summarize the role of WIPI proteins and their C. elegans homologues with regard to the molecular basis of aging. As the development of strategies on how to increase health span in humans is increasingly appreciated, we speculate that targeting WIPI protein function might represent a therapeutic opportunity to fight and delay the onset of age-related human diseases.

No MeSH data available.


Related in: MedlinePlus