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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

Autophagy and longevity control in C. elegans. The four human WIPI proteins are represented by two homologues, ATG-18 (homologue of WIPI1 and WIPI2) and EPG-6 (homologue of WIPI3 and WIPI4) in C. elegans, both of which are considered to be required for autophagy-controlled longevity (A). Hormones and nutrients (e.g. amino acids) control both autophagy and longevity in C. elegans (B). Upon hormone binding to and dimerization of DAF-2, the C. elegans orthologue of mammalian insulin/IGF-1 receptor (IGFR), AKT (also AKT in mammals) is activated via AGE-1 (PI3KC1 in mammals) to phosphorylate the transcription factor DAF-16. Phospho-DAF-16 is unable to localize to the nucleus. In the absence of AKT-mediated phosphorylation, DAF-16 localizes to the nucleus and fulfills its transcriptional transactivation activity on a large subset of genes controlling stress resistance and survival, by upregulation of mediators required for detoxification, anti-inflammation and lipolysis (lipl-4, LIPN in mammals). DAF-16 is further critically controlled by TOR (mTOR in mammals, a well-known target of AKT-mediated signaling). Upon nutrient availability (e.g. amino acids), TOR inhibits both transcription factors DAF-16 and PHA-4 (FOXA in mammals). Subsequently unc-51 (ATG1 in yeast and ULK in mammals) transcription is inhibited, preventing full autophagic activity. Interdependently, lipolysis and autophagy control longevity in C. elegans. The schematic drawings of C. elegans, plasma membrane, receptor, nuclear envelope and DNA were obtained from Motifolio.
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cells-04-00202-f003: Autophagy and longevity control in C. elegans. The four human WIPI proteins are represented by two homologues, ATG-18 (homologue of WIPI1 and WIPI2) and EPG-6 (homologue of WIPI3 and WIPI4) in C. elegans, both of which are considered to be required for autophagy-controlled longevity (A). Hormones and nutrients (e.g. amino acids) control both autophagy and longevity in C. elegans (B). Upon hormone binding to and dimerization of DAF-2, the C. elegans orthologue of mammalian insulin/IGF-1 receptor (IGFR), AKT (also AKT in mammals) is activated via AGE-1 (PI3KC1 in mammals) to phosphorylate the transcription factor DAF-16. Phospho-DAF-16 is unable to localize to the nucleus. In the absence of AKT-mediated phosphorylation, DAF-16 localizes to the nucleus and fulfills its transcriptional transactivation activity on a large subset of genes controlling stress resistance and survival, by upregulation of mediators required for detoxification, anti-inflammation and lipolysis (lipl-4, LIPN in mammals). DAF-16 is further critically controlled by TOR (mTOR in mammals, a well-known target of AKT-mediated signaling). Upon nutrient availability (e.g. amino acids), TOR inhibits both transcription factors DAF-16 and PHA-4 (FOXA in mammals). Subsequently unc-51 (ATG1 in yeast and ULK in mammals) transcription is inhibited, preventing full autophagic activity. Interdependently, lipolysis and autophagy control longevity in C. elegans. The schematic drawings of C. elegans, plasma membrane, receptor, nuclear envelope and DNA were obtained from Motifolio.

Mentions: From this it was deduced that both ATG-18 as well as EPG-6 have an essential function in autophagy and the degradation of engulfed apoptotic cell corpses in C. elegans. Hence the functional contribution of both ATG-18 and EPG-6 in autophagy is considered to define the lifespan of C. elegans and to contribute to longevity (Figure 3A).


WIPI-Mediated Autophagy and Longevity.

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

Autophagy and longevity control in C. elegans. The four human WIPI proteins are represented by two homologues, ATG-18 (homologue of WIPI1 and WIPI2) and EPG-6 (homologue of WIPI3 and WIPI4) in C. elegans, both of which are considered to be required for autophagy-controlled longevity (A). Hormones and nutrients (e.g. amino acids) control both autophagy and longevity in C. elegans (B). Upon hormone binding to and dimerization of DAF-2, the C. elegans orthologue of mammalian insulin/IGF-1 receptor (IGFR), AKT (also AKT in mammals) is activated via AGE-1 (PI3KC1 in mammals) to phosphorylate the transcription factor DAF-16. Phospho-DAF-16 is unable to localize to the nucleus. In the absence of AKT-mediated phosphorylation, DAF-16 localizes to the nucleus and fulfills its transcriptional transactivation activity on a large subset of genes controlling stress resistance and survival, by upregulation of mediators required for detoxification, anti-inflammation and lipolysis (lipl-4, LIPN in mammals). DAF-16 is further critically controlled by TOR (mTOR in mammals, a well-known target of AKT-mediated signaling). Upon nutrient availability (e.g. amino acids), TOR inhibits both transcription factors DAF-16 and PHA-4 (FOXA in mammals). Subsequently unc-51 (ATG1 in yeast and ULK in mammals) transcription is inhibited, preventing full autophagic activity. Interdependently, lipolysis and autophagy control longevity in C. elegans. The schematic drawings of C. elegans, plasma membrane, receptor, nuclear envelope and DNA were obtained from Motifolio.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4493456&req=5

cells-04-00202-f003: Autophagy and longevity control in C. elegans. The four human WIPI proteins are represented by two homologues, ATG-18 (homologue of WIPI1 and WIPI2) and EPG-6 (homologue of WIPI3 and WIPI4) in C. elegans, both of which are considered to be required for autophagy-controlled longevity (A). Hormones and nutrients (e.g. amino acids) control both autophagy and longevity in C. elegans (B). Upon hormone binding to and dimerization of DAF-2, the C. elegans orthologue of mammalian insulin/IGF-1 receptor (IGFR), AKT (also AKT in mammals) is activated via AGE-1 (PI3KC1 in mammals) to phosphorylate the transcription factor DAF-16. Phospho-DAF-16 is unable to localize to the nucleus. In the absence of AKT-mediated phosphorylation, DAF-16 localizes to the nucleus and fulfills its transcriptional transactivation activity on a large subset of genes controlling stress resistance and survival, by upregulation of mediators required for detoxification, anti-inflammation and lipolysis (lipl-4, LIPN in mammals). DAF-16 is further critically controlled by TOR (mTOR in mammals, a well-known target of AKT-mediated signaling). Upon nutrient availability (e.g. amino acids), TOR inhibits both transcription factors DAF-16 and PHA-4 (FOXA in mammals). Subsequently unc-51 (ATG1 in yeast and ULK in mammals) transcription is inhibited, preventing full autophagic activity. Interdependently, lipolysis and autophagy control longevity in C. elegans. The schematic drawings of C. elegans, plasma membrane, receptor, nuclear envelope and DNA were obtained from Motifolio.
Mentions: From this it was deduced that both ATG-18 as well as EPG-6 have an essential function in autophagy and the degradation of engulfed apoptotic cell corpses in C. elegans. Hence the functional contribution of both ATG-18 and EPG-6 in autophagy is considered to define the lifespan of C. elegans and to contribute to longevity (Figure 3A).

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