Article ; Online: Inhibition of class I PI3K enhances chaperone-mediated autophagy.
2020 Volume 219, Issue 12
Abstract: 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- ... ...
| Abstract | 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. |
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| MeSH term(s) | 3-Phosphoinositide-Dependent Protein Kinases/genetics ; 3-Phosphoinositide-Dependent Protein Kinases/metabolism ; Animals ; Autophagy ; Glial Fibrillary Acidic Protein/genetics ; Glial Fibrillary Acidic Protein/metabolism ; Humans ; Lysosomes/genetics ; Lysosomes/metabolism ; Mice ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; NIH 3T3 Cells ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism | |||||
| Chemical Substances | GFAP protein, human ; Glial Fibrillary Acidic Protein ; Molecular Chaperones ; glial fibrillary astrocytic protein, mouse ; 3-Phosphoinositide-Dependent Protein Kinases (EC 2.7.11.1) ; PDPK1 protein, human (EC 2.7.11.1) ; Pdpk1 protein, mouse (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) | |||||
| Language | English | |||||
| Publishing date | 2020-10-10 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 218154-x | |||||
| ISSN | 1540-8140 ; 0021-9525 | |||||
| ISSN (online) | 1540-8140 | |||||
| ISSN | 0021-9525 | |||||
| DOI | 10.1083/jcb.202001031 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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