PMID- 33048163
OWN - NLM
STAT- MEDLINE
DCOM- 20210330
LR  - 20230103
IS  - 1540-8140 (Electronic)
IS  - 0021-9525 (Print)
IS  - 0021-9525 (Linking)
VI  - 219
IP  - 12
DP  - 2020 Dec 7
TI  - Inhibition of class I PI3K enhances chaperone-mediated autophagy.
LID - 10.1083/jcb.202001031 [doi]
LID - e202001031
AB  - 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.
CI  - (c) 2020 Endicott et al.
FAU - Endicott, S Joseph
AU  - Endicott SJ
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI.
FAU - Ziemba, Zachary J
AU  - Ziemba ZJ
AD  - College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, 
      MI.
FAU - Beckmann, Logan J
AU  - Beckmann LJ
AD  - College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, 
      MI.
FAU - Boynton, Dennis N
AU  - Boynton DN
AD  - College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, 
      MI.
FAU - Miller, Richard A
AU  - Miller RA
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI.
AD  - University of Michigan Geriatrics Center, Ann Arbor, MI.
LA  - eng
GR  - P30 AG024824/AG/NIA NIH HHS/United States
GR  - T32 AG000114/AG/NIA NIH HHS/United States
GR  - U01 AG022303/AG/NIA NIH HHS/United States
GR  - U19 AG023122/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Biol
JT  - The Journal of cell biology
JID - 0375356
RN  - 0 (GFAP protein, human)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (Molecular Chaperones)
RN  - 0 (glial fibrillary astrocytic protein, mouse)
RN  - EC 2.7.11.1 (3-Phosphoinositide-Dependent Protein Kinases)
RN  - EC 2.7.11.1 (PDPK1 protein, human)
RN  - EC 2.7.11.1 (Pdpk1 protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - 3-Phosphoinositide-Dependent Protein Kinases/genetics/metabolism
MH  - Animals
MH  - *Autophagy
MH  - Glial Fibrillary Acidic Protein/genetics/metabolism
MH  - Humans
MH  - Lysosomes/genetics/metabolism
MH  - Mice
MH  - Molecular Chaperones/genetics/*metabolism
MH  - NIH 3T3 Cells
MH  - Phosphatidylinositol 3-Kinases/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
PMC - PMC7557678
EDAT- 2020/10/14 06:00
MHDA- 2021/03/31 06:00
PMCR- 2021/04/13
CRDT- 2020/10/13 12:12
PHST- 2020/02/19 00:00 [received]
PHST- 2020/04/14 00:00 [revised]
PHST- 2020/09/09 00:00 [accepted]
PHST- 2020/10/13 12:12 [entrez]
PHST- 2020/10/14 06:00 [pubmed]
PHST- 2021/03/31 06:00 [medline]
PHST- 2021/04/13 00:00 [pmc-release]
AID - 211459 [pii]
AID - jcb.202001031 [pii]
AID - 10.1083/jcb.202001031 [doi]
PST - ppublish
SO  - J Cell Biol. 2020 Dec 7;219(12):e202001031. doi: 10.1083/jcb.202001031.