Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy

Esperanza Arias-Perez, Hiroshi Koga, Antonio Diaz, Enric Mocholi, Bindi Patel, Ana Maria Cuervo

Research output: Contribution to journalArticle

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Abstract

Chaperone-mediated autophagy (CMA), a selective form of degradation of cytosolic proteins in lysosomes, contributes to maintenance of proteostasis and to the cellular adaptation to stress. CMA substrates are delivered by a cytosolic chaperone to the lysosomal surface, where, upon unfolding, they are internalized through a membrane translocation complex. The molecular components that participate in CMA substrate targeting and translocation are well characterized, but those involved in CMA regulation remain mostly unknown. In this study, we have identified that CMA is under the positive control of the phosphatase PHLPP1 that associates with the lysosomal membrane and counteracts the inhibitory effect of mTORC2 on CMA. Lysosomal Akt, a target of the mTORC2/PHLPP1 kinase-phosphatase pair, modulates CMA activity by controlling the dynamics of assembly and disassembly of the CMA translocation complex at the lysosomal membrane. The lysosomal mTORC2/PHLPP1/Akt axis could become a target to restore CMA dysfunction in aging and disease.

Original languageEnglish (US)
Pages (from-to)270-284
Number of pages15
JournalMolecular Cell
Volume59
Issue number2
DOIs
StatePublished - Jul 16 2015

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Autophagy
Phosphoric Monoester Hydrolases
Membranes
TOR complex 2
Lysosomes
Proteolysis
Phosphotransferases
Maintenance

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy. / Arias-Perez, Esperanza; Koga, Hiroshi; Diaz, Antonio; Mocholi, Enric; Patel, Bindi; Cuervo, Ana Maria.

In: Molecular Cell, Vol. 59, No. 2, 16.07.2015, p. 270-284.

Research output: Contribution to journalArticle

Arias-Perez, Esperanza ; Koga, Hiroshi ; Diaz, Antonio ; Mocholi, Enric ; Patel, Bindi ; Cuervo, Ana Maria. / Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy. In: Molecular Cell. 2015 ; Vol. 59, No. 2. pp. 270-284.
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