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Nat. Cell Biol., Jan 24 2024, | https://doi.org/10.1038/s41556-023-01338-y
p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson-Gilford progeria syndrome
Sung Min Son1,2, So Jung Park1,2, Sophia Y. Breusegem1, Delphine Larrieu1,3 & David C. Rubinsztein1,2
1Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
2UK Dementia Research Institute, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
3Department of Pharmacology, University of Cambridge, Cambridge, UK.
Corresponding author : Correspondence to David C. Rubinsztein.
Abstract
The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth, metabolism and autophagy. Multiple pathways modulate mTORC1 in response to nutrients. Here we describe that nucleus-cytoplasmic shuttling of p300/EP300 regulates mTORC1 activity in response to amino acid or glucose levels. Depletion of these nutrients causes cytoplasm-to-nucleus relocalization of p300 that decreases acetylation of the mTORC1 component raptor, thereby reducing mTORC1 activity and activating autophagy. This is mediated by AMP-activated protein kinase-dependent phosphorylation of p300 at serine 89. Nutrient addition to starved cells results in protein phosphatase 2A-dependent dephosphorylation of nuclear p300, enabling its CRM1-dependent export to the cytoplasm to mediate mTORC1 reactivation. p300 shuttling regulates mTORC1 in most cell types and occurs in response to altered nutrients in diverse mouse tissues. Interestingly, p300 cytoplasm-nucleus shuttling is altered in cells from patients with Hutchinson-Gilford progeria syndrome. p300 mislocalization by the disease-causing protein, progerin, activates mTORC1 and inhibits autophagy, phenotypes that are normalized by modulating p300 shuttling. These results reveal how nutrients regulate mTORC1, a cytoplasmic complex, by shuttling its positive regulator p300 in and out of the nucleus, and how this pathway is misregulated in Hutchinson-Gilford progeria syndrome, causing mTORC1 hyperactivation and defective autophagy.
논문정보
- Research article
- 2024년 01월 (BRIC 등록일 2024-01-26)
- 국외 연구진
- 생명과학 > 신경생물학
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