{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Cheratta AR"],"funding":["Wellcome Trust"],"pagination":["110761"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9108549"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["39(5)"],"pubmed_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."],"journal":["Cell reports"],"pubmed_title":["Caspase cleavage and nuclear retention of the energy sensor AMPK-α1 during apoptosis."],"pmcid":["PMC9108549"],"funding_grant_id":["204766/Z/16/Z","204766"],"pubmed_authors":["Atrih A","Alakkal A","Rezgui R","Thayyullathil F","Hawley SA","Cheratta AR","Ross FA","Hardie DG","Galadari S","Subburayan K","Pallichankandy S","Gray A","Lamont DJ"],"additional_accession":[]},"is_claimable":false,"name":"Caspase cleavage and nuclear retention of the energy sensor AMPK-α1 during apoptosis.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 May","modification":"2026-05-09T23:46:06.22Z","creation":"2025-04-04T22:15:46.532Z"},"accession":"S-EPMC9108549","cross_references":{"pubmed":["35508122"],"doi":["10.1016/j.celrep.2022.110761"]}}