Lysosomal mTORC2/PHLPP1/Akt regulate chaperone-mediated autophagy
What this study shows
Extends the mTOR-autophagy relationship to a third form of autophagy that the Atlas otherwise does not cover, and reverses two of its usual terms. Here it is mTORC2, not mTORC1, that sits on the lysosomal membrane, and it inhibits chaperone-mediated autophagy through Akt, while the phosphatase PHLPP1 counteracts it; the balance controls assembly and disassembly of the translocation complex that pulls single proteins into the lysosome. Boundary: mechanism in cells and rodent liver; the claim that restoring this axis helps in ageing or disease is proposed, not tested here.
Abstract
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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.
Read the full abstract on PubMed →At a glance
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| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Mouse liver, rat liver, cell lines (NIH 3T3)) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mouse liver, rat liver, cell lines (NIH 3T3) |
| Journal | Molecular Cell |
| Year | 2015 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1016/j.molcel.2015.05.030 · PMID 26118642 |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
Pathway relations
Supports
mTORC2 activates Akt/PKBStrongest evidence: A (Animal model) · settled in the literature · Status: Proposed
plausible in people, not shown directly
Mammalian cell studies, cancer cells and one mouse and rat liver study (ARI2015). Ser473 phosphorylation is shown in cells. The glucose consequence of losing it comes from mouse work (LAM2012) and has not been measured in people.
People in the Atlas
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Showed that mTORC2, working with PHLPP1 and Akt at the lysosome, regulates chaperone-mediated autophagy
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Worked out much of the machinery of chaperone-mediated autophagy, a pathway first described in Fred Dice's laboratory, and showed it declines with age
More: 4 other authors
No profile yet: Koga H, Diaz A, Mocholi E, Patel B
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Topics
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | Genetic and pharmacological manipulation of mTORC2, PHLPP1 and Akt |
| Target | Lysosomal mTORC2/PHLPP1/Akt axis; chaperone-mediated autophagy |
| Model | Mouse and rat liver; NIH3T3 cells |
| Effect | mTORC2 inhibits chaperone-mediated autophagy via lysosomal Akt, while PHLPP1 counteracts it. |
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