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Therapeutic targeting of autophagy in neurodegenerative and infectious diseases.

Rubinsztein DC, Bento CF, Deretic V - J. Exp. Med. (2015)

Bottom Line: Autophagy is a conserved process that uses double-membrane vesicles to deliver cytoplasmic contents to lysosomes for degradation.The beneficial roles of autophagy can now be extended to supporting cell survival and regulating inflammation.Preclinical data supporting the potential therapeutic utility of autophagy modulation in such conditions is accumulating.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge CB2 OSP, England, UK dcr1000@cam.ac.uk vderetic@salud.unm.edu.

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Schematic of autophagy. Activation of AMPK and/or inhibition of mTORC1 by various stress signals induces activation of the ATG1–ULK1 complex, which positively regulates the activity of the VPS34 complex via phosphorylation-dependent mechanisms. Class III PI3K VPS34 provides PI3P to the phagophore, which seems to define the LC3-lipidation sites by assisting in the recruitment of the ATG12–ATG5–ATG16L1 complex to the membrane (asterisks). After the binding of ATG12–ATG5–ATG16L1 complex to the phagophore and LC3 conjugation to PE (LC3-II), the membrane elongates and engulfs portions of the cytoplasm, ultimately leading to the formation of the complete autophagosome. Proteins such as p62, NDP52, and NBR1 confer substrate selectivity to the pathway by establishing a bridge between LC3-II and specific ubiquitinated cargo (e.g., aggregates, microbes, mitochondria, and peroxisomes), through their LIR and UBA domains, respectively. In the final step of the process, autophagosomes fuse with lysosomes, resulting in the degradation of the vesicle contents. AMPK, AMP-activated protein kinase; mTORC1, mechanistic target of rapamycin complex 1; ULK, Unc-51-like kinase; VPS34, phosphatidylinositol 3-kinase VPS34; PI3P, phosphatidylinositol 3-phosphate; PE, phosphatidylethanolamine; LIR, LC3-interacting region; UBA, ubiquitin associated domain.
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fig1: Schematic of autophagy. Activation of AMPK and/or inhibition of mTORC1 by various stress signals induces activation of the ATG1–ULK1 complex, which positively regulates the activity of the VPS34 complex via phosphorylation-dependent mechanisms. Class III PI3K VPS34 provides PI3P to the phagophore, which seems to define the LC3-lipidation sites by assisting in the recruitment of the ATG12–ATG5–ATG16L1 complex to the membrane (asterisks). After the binding of ATG12–ATG5–ATG16L1 complex to the phagophore and LC3 conjugation to PE (LC3-II), the membrane elongates and engulfs portions of the cytoplasm, ultimately leading to the formation of the complete autophagosome. Proteins such as p62, NDP52, and NBR1 confer substrate selectivity to the pathway by establishing a bridge between LC3-II and specific ubiquitinated cargo (e.g., aggregates, microbes, mitochondria, and peroxisomes), through their LIR and UBA domains, respectively. In the final step of the process, autophagosomes fuse with lysosomes, resulting in the degradation of the vesicle contents. AMPK, AMP-activated protein kinase; mTORC1, mechanistic target of rapamycin complex 1; ULK, Unc-51-like kinase; VPS34, phosphatidylinositol 3-kinase VPS34; PI3P, phosphatidylinositol 3-phosphate; PE, phosphatidylethanolamine; LIR, LC3-interacting region; UBA, ubiquitin associated domain.

Mentions: Macroautophagy is one of the major routes for the degradation of intracytoplasmic contents, including proteins and organelles such as mitochondria. The earliest morphologically recognizable intermediates in this pathway are phagophores, which evolve into double-membraned, sac-shaped structures. After the edges of the phagophores extend and fuse, engulfing a portion of cytoplasm, they become known as autophagosomes. These are then trafficked along microtubules in a direction that is biased toward the perinuclear microtubule-organizing center, where the lysosomes are clustered. This brings the autophagosomes close to lysosomes, enabling fusion of these different organelles, after which the lysosomal hydrolases degrade the autophagic contents (Fig. 1).


Therapeutic targeting of autophagy in neurodegenerative and infectious diseases.

Rubinsztein DC, Bento CF, Deretic V - J. Exp. Med. (2015)

Schematic of autophagy. Activation of AMPK and/or inhibition of mTORC1 by various stress signals induces activation of the ATG1–ULK1 complex, which positively regulates the activity of the VPS34 complex via phosphorylation-dependent mechanisms. Class III PI3K VPS34 provides PI3P to the phagophore, which seems to define the LC3-lipidation sites by assisting in the recruitment of the ATG12–ATG5–ATG16L1 complex to the membrane (asterisks). After the binding of ATG12–ATG5–ATG16L1 complex to the phagophore and LC3 conjugation to PE (LC3-II), the membrane elongates and engulfs portions of the cytoplasm, ultimately leading to the formation of the complete autophagosome. Proteins such as p62, NDP52, and NBR1 confer substrate selectivity to the pathway by establishing a bridge between LC3-II and specific ubiquitinated cargo (e.g., aggregates, microbes, mitochondria, and peroxisomes), through their LIR and UBA domains, respectively. In the final step of the process, autophagosomes fuse with lysosomes, resulting in the degradation of the vesicle contents. AMPK, AMP-activated protein kinase; mTORC1, mechanistic target of rapamycin complex 1; ULK, Unc-51-like kinase; VPS34, phosphatidylinositol 3-kinase VPS34; PI3P, phosphatidylinositol 3-phosphate; PE, phosphatidylethanolamine; LIR, LC3-interacting region; UBA, ubiquitin associated domain.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig1: Schematic of autophagy. Activation of AMPK and/or inhibition of mTORC1 by various stress signals induces activation of the ATG1–ULK1 complex, which positively regulates the activity of the VPS34 complex via phosphorylation-dependent mechanisms. Class III PI3K VPS34 provides PI3P to the phagophore, which seems to define the LC3-lipidation sites by assisting in the recruitment of the ATG12–ATG5–ATG16L1 complex to the membrane (asterisks). After the binding of ATG12–ATG5–ATG16L1 complex to the phagophore and LC3 conjugation to PE (LC3-II), the membrane elongates and engulfs portions of the cytoplasm, ultimately leading to the formation of the complete autophagosome. Proteins such as p62, NDP52, and NBR1 confer substrate selectivity to the pathway by establishing a bridge between LC3-II and specific ubiquitinated cargo (e.g., aggregates, microbes, mitochondria, and peroxisomes), through their LIR and UBA domains, respectively. In the final step of the process, autophagosomes fuse with lysosomes, resulting in the degradation of the vesicle contents. AMPK, AMP-activated protein kinase; mTORC1, mechanistic target of rapamycin complex 1; ULK, Unc-51-like kinase; VPS34, phosphatidylinositol 3-kinase VPS34; PI3P, phosphatidylinositol 3-phosphate; PE, phosphatidylethanolamine; LIR, LC3-interacting region; UBA, ubiquitin associated domain.
Mentions: Macroautophagy is one of the major routes for the degradation of intracytoplasmic contents, including proteins and organelles such as mitochondria. The earliest morphologically recognizable intermediates in this pathway are phagophores, which evolve into double-membraned, sac-shaped structures. After the edges of the phagophores extend and fuse, engulfing a portion of cytoplasm, they become known as autophagosomes. These are then trafficked along microtubules in a direction that is biased toward the perinuclear microtubule-organizing center, where the lysosomes are clustered. This brings the autophagosomes close to lysosomes, enabling fusion of these different organelles, after which the lysosomal hydrolases degrade the autophagic contents (Fig. 1).

Bottom Line: Autophagy is a conserved process that uses double-membrane vesicles to deliver cytoplasmic contents to lysosomes for degradation.The beneficial roles of autophagy can now be extended to supporting cell survival and regulating inflammation.Preclinical data supporting the potential therapeutic utility of autophagy modulation in such conditions is accumulating.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge CB2 OSP, England, UK dcr1000@cam.ac.uk vderetic@salud.unm.edu.

Show MeSH
Related in: MedlinePlus