@article{946cb397a5604d21b13ca9244453f16e,
title = "Caspase cleavage and nuclear retention of the energy sensor AMPK-α1 during apoptosis",
abstract = "AMP-activated protein kinase (AMPK) coordinates energy homeostasis during metabolic and energy stress. We report that the catalytic subunit isoform AMPK-α1 (but not α2) is cleaved by caspase-3 at an early stage during induction of apoptosis. AMPK-α1 cleavage occurs following Asp529, generating an ∼58-kDa N-terminal fragment (cl-AMPK-α1) and leading to the precise excision of the nuclear export sequence (NES) from the C-terminal end. This cleavage does not affect (1) the stability of pre-formed heterotrimeric complexes, (2) the ability of cl-AMPK-α1 to become phosphorylated and activated by the upstream kinases LKB1 or CaMKK2, or (3) allosteric activation by AMP or A-769662. Importantly, cl-AMPK-α1 is only detectable in the nucleus, consistent with removal of the NES, and ectopic expression of cleavage-resistant D529A-mutant AMPK-α1 promotes cell death induced by cytotoxic agents. Thus, we have elucidated a non-canonical mechanism of AMPK activation within the nucleus, which protects cells against death induced by DNA damage.",
keywords = "AMPK, CP: Cell biology, CP: Molecular biology, anti-Fas, apoptosis, caspase, catalytic, cl-AMPK-α1, cleavage, etoposide, kinase, nuclear export sequence",
author = "Cheratta, {Anees Rahman} and Faisal Thayyullathil and Hawley, {Simon A.} and Ross, {Fiona A.} and Abdelmajdid Atrih and Lamont, {Douglas J.} and Siraj Pallichankandy and Karthikeyan Subburayan and Ameer Alakkal and Rachid Rezgui and Alex Gray and Hardie, {D. Grahame} and Sehamuddin Galadari",
note = "Funding Information: This work was financially supported by grants from New York University Abu Dhabi Research Enhancement Fund ( RE252 ) to S.G. We also acknowledge the NYUAD Core Technology Platform for their support. D.G.H. was supported by a Wellcome Trust Investigator Award ( 204766 ). We are very grateful to Sang Jeon Chung (Sungkyunkwan University) for the plasmid expressing active human caspase-3. Funding Information: This work was financially supported by grants from New York University Abu Dhabi Research Enhancement Fund (RE252) to S.G. We also acknowledge the NYUAD Core Technology Platform for their support. D.G.H. was supported by a Wellcome Trust Investigator Award (204766). We are very grateful to Sang Jeon Chung (Sungkyunkwan University) for the plasmid expressing active human caspase-3. A.R.C. designed and performed most of the experiments. F.T. generated plasmids and carried out related experiments. A.R.C. wrote the initial manuscript. S.A.H. and F.A.R. carried out bacterial expression and phosphorylation studies and prepared samples for MS. A.A. and D.J.L. advised upon and performed MS analysis. R.R. performed confocal experiments. K.S. S.P. and A.A. contributed in analyzing the results. A.G. constructed the AMPK knockout HEK-293 cells. S.G. and D.G.H. made valuable suggestions in designing the study. All authors approved and commented on the manuscript. The authors declare no competing interests. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We worked to ensure diversity in experimental samples through the selection of the cell lines. We worked to ensure diversity in experimental samples through the selection of the genomic datasets. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = may,
day = "3",
doi = "10.1016/j.celrep.2022.110761",
language = "English (US)",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}