Repository logo
 

p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson-Gilford progeria syndrome.

Published version
Peer-reviewed

Repository DOI


Change log

Authors

Park, So Jung 
Breusegem, Sophia Y 
Rubinsztein, David C  ORCID logo  https://orcid.org/0000-0001-5002-5263

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.

Description

Acknowledgements: We thank F. Siddiqi and L. Wrobel for help with mouse samples. We thank E. Stamatakou for advice and technical support for KO cell lines using CRISPR–Cas9 editing. We thank A. Djajadikerta for making the SRAI–hLC3B construct. We are grateful for funding from UK Dementia Research Institute (funded by the Medical Research Council, Alzheimer’s Research UK and the Alzheimer’s Society) and Parkinson’s UK (D.C.R.). D.L. and S.Y.B. were funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society grant no. 206242/Z/17/Z. This research was also supported by the NIHR Cambridge Biomedical Research Centre (grant no. NIHR203312). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.


Funder: UK Dementia Research Institute NIHR Cambridge Biomedical Research Centre (NIHR203312)


Funder: Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society 206242/Z/17/Z

Keywords

Humans, Mice, Animals, Mechanistic Target of Rapamycin Complex 1, Progeria, Active Transport, Cell Nucleus, Regulatory-Associated Protein of mTOR, Amino Acids, Lamin Type A

Journal Title

Nat Cell Biol

Conference Name

Journal ISSN

1465-7392
1476-4679

Volume Title

26

Publisher

Springer Science and Business Media LLC
Sponsorship
UK Dementia Research Institute (Unknown)
Wellcome Trust (206242/Z/17/Z)
We are grateful for funding from UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society) and Parkinson’s UK (D.C.R.). D.L. and S. Y. B. were funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society 206242/Z/17/Z. This research was also supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312).