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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

Working model: The PI3P-effector function of human WIPI proteins at the nascent autophagosome. Initiation of ER-localized PI3P production is regulated by the differential actions of AMPK and mTORC1 on the ULK1 complex. Following AMPK-mediated ULK1 activation, the lipid kinase PI3KC3, in complex with Beclin 1, ATG14, and Vps15, is activated to produce PI3P. Upon PI3P production, WIPI proteins are rapidly recruited to the site of autophagosome formation, where WIPI proteins specifically bind PI3P and permit the subsequent formation and proper elongation of the phagophore, as suggested for WIPI1, WIPI2, and WIPI4. Here, WIPI2B recruits the ATG12-5/ATG16 complex via binding to ATG16, permitting LC3 conjugation to PE. It is unknown whether or not WIPI3 is recruited to the phagophore. WIPI1 and WIPI2 have been detected at both the inner and outer membrane of autophagosomes. WIPI1 was further shown to colocalize with the lysosomal protein LAMP1; however, WIPI2 was not found to colocalize with LAMP2. WIPI4 might dissociate in the process of autophagosome closure and maturation. The schematic drawings of the ER was obtained from Motifolio.
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cells-04-00202-f002: Working model: The PI3P-effector function of human WIPI proteins at the nascent autophagosome. Initiation of ER-localized PI3P production is regulated by the differential actions of AMPK and mTORC1 on the ULK1 complex. Following AMPK-mediated ULK1 activation, the lipid kinase PI3KC3, in complex with Beclin 1, ATG14, and Vps15, is activated to produce PI3P. Upon PI3P production, WIPI proteins are rapidly recruited to the site of autophagosome formation, where WIPI proteins specifically bind PI3P and permit the subsequent formation and proper elongation of the phagophore, as suggested for WIPI1, WIPI2, and WIPI4. Here, WIPI2B recruits the ATG12-5/ATG16 complex via binding to ATG16, permitting LC3 conjugation to PE. It is unknown whether or not WIPI3 is recruited to the phagophore. WIPI1 and WIPI2 have been detected at both the inner and outer membrane of autophagosomes. WIPI1 was further shown to colocalize with the lysosomal protein LAMP1; however, WIPI2 was not found to colocalize with LAMP2. WIPI4 might dissociate in the process of autophagosome closure and maturation. The schematic drawings of the ER was obtained from Motifolio.

Mentions: ULK is further phosphorylated by AMPK (AMP-activated protein kinase), an evolutionarily conserved energy sensor that is activated when low ATP:AMP ratios prevail in the cell. To compensate energy shortage, AMPK phosphorylates ULK at activatory phosphorylation sites to directly initiate autophagy. AMPK further activates autophagy indirectly by inhibiting mTORC1 [21]. Although the signaling network regulation of ULK phosphorylation is far from being understood, it was recognized that ULK activation can lead to the phosphorylation of Beclin 1 in the PI3KC3 complex [19,20], subsequently activating PI3KC3 to produce PI3P [22]. PI3P production is considered to occur majorly at the endoplasmic reticulum, where it is recognized by WIPI proteins that become rapidly recruited to the nascent autophagosome (Figure 2) [14].


WIPI-Mediated Autophagy and Longevity.

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

Working model: The PI3P-effector function of human WIPI proteins at the nascent autophagosome. Initiation of ER-localized PI3P production is regulated by the differential actions of AMPK and mTORC1 on the ULK1 complex. Following AMPK-mediated ULK1 activation, the lipid kinase PI3KC3, in complex with Beclin 1, ATG14, and Vps15, is activated to produce PI3P. Upon PI3P production, WIPI proteins are rapidly recruited to the site of autophagosome formation, where WIPI proteins specifically bind PI3P and permit the subsequent formation and proper elongation of the phagophore, as suggested for WIPI1, WIPI2, and WIPI4. Here, WIPI2B recruits the ATG12-5/ATG16 complex via binding to ATG16, permitting LC3 conjugation to PE. It is unknown whether or not WIPI3 is recruited to the phagophore. WIPI1 and WIPI2 have been detected at both the inner and outer membrane of autophagosomes. WIPI1 was further shown to colocalize with the lysosomal protein LAMP1; however, WIPI2 was not found to colocalize with LAMP2. WIPI4 might dissociate in the process of autophagosome closure and maturation. The schematic drawings of the ER was obtained from Motifolio.
© Copyright Policy
Related In: Results  -  Collection

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

cells-04-00202-f002: Working model: The PI3P-effector function of human WIPI proteins at the nascent autophagosome. Initiation of ER-localized PI3P production is regulated by the differential actions of AMPK and mTORC1 on the ULK1 complex. Following AMPK-mediated ULK1 activation, the lipid kinase PI3KC3, in complex with Beclin 1, ATG14, and Vps15, is activated to produce PI3P. Upon PI3P production, WIPI proteins are rapidly recruited to the site of autophagosome formation, where WIPI proteins specifically bind PI3P and permit the subsequent formation and proper elongation of the phagophore, as suggested for WIPI1, WIPI2, and WIPI4. Here, WIPI2B recruits the ATG12-5/ATG16 complex via binding to ATG16, permitting LC3 conjugation to PE. It is unknown whether or not WIPI3 is recruited to the phagophore. WIPI1 and WIPI2 have been detected at both the inner and outer membrane of autophagosomes. WIPI1 was further shown to colocalize with the lysosomal protein LAMP1; however, WIPI2 was not found to colocalize with LAMP2. WIPI4 might dissociate in the process of autophagosome closure and maturation. The schematic drawings of the ER was obtained from Motifolio.
Mentions: ULK is further phosphorylated by AMPK (AMP-activated protein kinase), an evolutionarily conserved energy sensor that is activated when low ATP:AMP ratios prevail in the cell. To compensate energy shortage, AMPK phosphorylates ULK at activatory phosphorylation sites to directly initiate autophagy. AMPK further activates autophagy indirectly by inhibiting mTORC1 [21]. Although the signaling network regulation of ULK phosphorylation is far from being understood, it was recognized that ULK activation can lead to the phosphorylation of Beclin 1 in the PI3KC3 complex [19,20], subsequently activating PI3KC3 to produce PI3P [22]. PI3P production is considered to occur majorly at the endoplasmic reticulum, where it is recognized by WIPI proteins that become rapidly recruited to the nascent autophagosome (Figure 2) [14].

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