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Inhibition of class I PI3K enhances chaperone-mediated autophagy
Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557678/ https://www.ncbi.nlm.nih.gov/pubmed/33048163 http://dx.doi.org/10.1083/jcb.202001031 |
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author | Endicott, S. Joseph Ziemba, Zachary J. Beckmann, Logan J. Boynton, Dennis N. Miller, Richard A. |
author_facet | Endicott, S. Joseph Ziemba, Zachary J. Beckmann, Logan J. Boynton, Dennis N. Miller, Richard A. |
author_sort | Endicott, S. Joseph |
collection | PubMed |
description | Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo. |
format | Online Article Text |
id | pubmed-7557678 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-75576782021-06-07 Inhibition of class I PI3K enhances chaperone-mediated autophagy Endicott, S. Joseph Ziemba, Zachary J. Beckmann, Logan J. Boynton, Dennis N. Miller, Richard A. J Cell Biol Article Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane. CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo. Rockefeller University Press 2020-10-13 /pmc/articles/PMC7557678/ /pubmed/33048163 http://dx.doi.org/10.1083/jcb.202001031 Text en © 2020 Endicott et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Endicott, S. Joseph Ziemba, Zachary J. Beckmann, Logan J. Boynton, Dennis N. Miller, Richard A. Inhibition of class I PI3K enhances chaperone-mediated autophagy |
title | Inhibition of class I PI3K enhances chaperone-mediated autophagy |
title_full | Inhibition of class I PI3K enhances chaperone-mediated autophagy |
title_fullStr | Inhibition of class I PI3K enhances chaperone-mediated autophagy |
title_full_unstemmed | Inhibition of class I PI3K enhances chaperone-mediated autophagy |
title_short | Inhibition of class I PI3K enhances chaperone-mediated autophagy |
title_sort | inhibition of class i pi3k enhances chaperone-mediated autophagy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557678/ https://www.ncbi.nlm.nih.gov/pubmed/33048163 http://dx.doi.org/10.1083/jcb.202001031 |
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