This is a paper I saw because it was cited in a paper which made the point that a high level of cytosolic acetyl-CoA reduces autophagy. It, however, is the first paper I have seen which suggests why HGPS results in the phenotype of accelerated aging. In particular it is the compartmentalisation of p300 which is one of the key Histone Acetyl Transferases which is used in the nucleus (inter alia) to acetylate the histone.
chatGPT:
Paper
Son et al., “p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson–Gilford progeria syndrome,” Nature Cell Biology, 2024.
Summary
This paper proposes a mechanism by which nutrient status regulates mTORC1 through the intracellular localisation of p300/EP300, a lysine acetyltransferase better known for nuclear chromatin regulation.
The core model is:
Nutrient deprivation → AMPK activation → p300 phosphorylation at S89 → p300 retained/imported into the nucleus via 14-3-3ζ → less cytoplasmic p300 → reduced raptor acetylation → reduced mTORC1 lysosomal activation → increased autophagy.
Then, after nutrient refeeding:
Nutrient replenishment → PP2A dephosphorylates p300 → CRM1-dependent nuclear export → p300 returns to cytoplasm → raptor acetylation increases → raptor–Rag binding and lysosomal mTORC1 activation increase → autophagy falls.
The authors show that p300 knockout cells have reduced raptor acetylation, reduced lysosomal mTOR localisation, reduced mTORC1 signalling, and increased autophagy. Re-expression of wild-type p300 rescues this, but catalytically inactive p300 does not, supporting the idea that p300 acetyltransferase activity is needed for nutrient-sensitive mTORC1 activation.
A key result is that nutrient starvation does not initially reduce total p300 activity; rather, it changes where p300 is located. Amino acid or glucose deprivation drives p300 from cytoplasm to nucleus, reducing its access to cytoplasmic substrates such as raptor. The figure on page 3 shows this visually: starvation enriches p300 in the nucleus, reduces p300–raptor colocalisation, lowers raptor acetylation, and suppresses S6K1/S6 phosphorylation. Cytoplasm-restricted p300 mutants blunt the normal fall in mTORC1 activity during starvation, implying that localisation is functionally important, not just correlative.
The mechanism appears broadly conserved across many cell lines and in mouse tissues. The page 4 figure shows that forced cytoplasmic p300 preserves residual mTORC1 activity during amino-acid deprivation in multiple cell types, and that fasting in mice increases nuclear p300 while lowering phospho-S6 in liver and muscle, with refeeding reversing the pattern.
The disease link is Hutchinson–Gilford progeria syndrome (HGPS). HGPS cells show altered nucleocytoplasmic transport, increased cytoplasmic p300, increased raptor and ATG7 acetylation, mTORC1 hyperactivation, and defective autophagy. The authors argue that progerin disrupts the p300 shuttling system, partly through impaired AMPK activation and increased CRM1-mediated nuclear export.
They further show that interventions which reduce cytoplasmic p300 activity or restore nuclear p300 localisation can improve cellular HGPS phenotypes. These include p300 inhibition with A485, AMPK activation with 991, and CRM1 inhibition with selinexor. The measured improvements include reduced DNA damage, improved lamin B1 levels, partial restoration of heterochromatin marker H3K9me3, reduced mTORC1 hyperactivation, improved autophagy, and reduced progerin levels.
What is novel?
The novelty is not simply that p300 regulates mTORC1; the same group and others had already connected p300, acetyl-CoA, raptor acetylation and mTORC1. The new contribution is the spatial control mechanism: p300’s shuttling between nucleus and cytoplasm acts as a nutrient-sensitive switch for mTORC1.
The most novel points are:
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A nuclear trafficking mechanism for a cytoplasmic nutrient pathway.
mTORC1 is cytoplasmic/lysosomal, but this paper argues that its nutrient response depends on moving its acetyltransferase regulator, p300, into and out of the nucleus. This is an elegant way to regulate raptor acetylation without necessarily changing total p300 abundance or intrinsic catalytic activity. -
AMPK–p300 S89–14-3-3ζ as a starvation import/retention pathway.
The paper identifies AMPK-dependent phosphorylation of p300 at serine 89 as a mechanism that favours nuclear localisation during nutrient deprivation. The S89A mutant blunts starvation-induced p300 nuclear transport and mTORC1 inhibition. -
PP2A–CRM1 as the refeeding export pathway.
On nutrient replenishment, PP2A dephosphorylates p300, enabling CRM1-dependent export back to the cytoplasm and mTORC1 reactivation. This gives a plausible reversible switch: AMPK pushes p300 nuclear during starvation; PP2A/CRM1 returns it to cytoplasm after feeding. -
A mechanistic explanation for mTORC1 hyperactivation in HGPS.
Previous work had shown mTORC1 hyperactivation and rapamycin benefit in HGPS, but this paper gives a more specific upstream mechanism: progerin disrupts p300 trafficking, leaving too much p300 in the cytoplasm, where it acetylates raptor and supports mTORC1 activation. -
A link between nuclear transport defects, epigenetic defects, autophagy failure and progerin persistence.
This is important because HGPS is often framed around nuclear lamina defects, DNA repair defects and chromatin defects. This paper connects those nuclear abnormalities to cytoplasmic mTORC1/autophagy through p300 localisation.
Critique
This is a strong mechanistic paper. The evidence chain is unusually complete: knockout/rescue experiments, catalytic-dead p300, localisation mutants, nutrient deprivation/refeeding, AMPK and PP2A perturbation, CRM1 involvement, multiple cell lines, mouse fasting/refeeding tissues, progerin-inducible cells and patient fibroblasts. The central mechanism is therefore well supported at the cell-biological level.
The main limitation is that the disease evidence remains mostly cellular. The HGPS findings are compelling in fibroblasts and induced progerin systems, but the paper does not show whether manipulating p300 shuttling improves organism-level HGPS pathology, cardiovascular disease, tissue stiffness, growth failure or survival in an HGPS animal model. That matters because HGPS pathology is systemic and heavily vascular.
A second limitation is that p300 is extremely pleiotropic. It acetylates histones and many non-histone proteins, including transcription factors and autophagy regulators. The authors focus on raptor acetylation as the key mTORC1 mechanism, but altered p300 localisation would also alter nuclear histone acetylation, transcription, DNA repair, inflammatory signalling and senescence programmes. The paper acknowledges that abnormal histone acetylation in HGPS may also contribute to phenotypes, but this is not exhaustively explored.
A third issue is therapeutic specificity. A485, 991 and selinexor are useful tools, but none is a clean “p300 shuttling drug.” A485 inhibits p300/CBP acetyltransferase activity broadly; AMPK activation has many downstream effects; CRM1 inhibition affects export of many proteins and can be toxic. So the rescue experiments support the pathway, but they do not yet establish a practical therapeutic route.
A fourth concern is causality in HGPS. The paper argues that progerin causes p300 mislocalisation, which causes mTORC1 hyperactivation and autophagy impairment. That is plausible, but progerin also causes DNA damage, nuclear deformation, mitochondrial dysfunction, altered chromatin and altered transport more generally. p300 mislocalisation may be a central amplifier rather than the initiating defect.
A fifth point is that nutrient deprivation/refeeding experiments are acute, whereas HGPS is chronic. It remains unclear whether repeated or chronic disruption of p300 shuttling behaves the same way as short-term amino acid/glucose starvation experiments. Chronic compensations in p300/CBP, acetyl-CoA metabolism, AMPK responsiveness and nuclear transport could alter the pathway.
Relevance to ageing biology
The paper is interesting because it links several ageing-relevant processes: mTORC1 hyperactivation, impaired autophagy, nuclear transport defects, p300/acetylation biology, AMPK signalling and progerin accumulation. It suggests that ageing-like pathology can arise not just from too much or too little p300 activity, but from p300 being in the wrong compartment.
For your acetyl-CoA / nuclear acetylation framework, the paper cuts both ways. It supports the importance of acetylation compartmentalisation, but it also shows that more cytoplasmic p300 and cytoplasmic acetylation can be harmful by driving mTORC1 and suppressing autophagy. In HGPS, the issue is not simply “low acetylation”; it is a misallocation of acetyltransferase activity: excessive cytoplasmic p300 activity with potentially insufficient or mispatterned nuclear chromatin acetylation.