Caspase cleavage and nuclear retention of the energy sensor AMPK-α1 during apoptosis

Anees Rahman Cheratta, Faisal Thayyullathil, Simon A. Hawley, Fiona A. Ross, Abdelmajdid Atrih, Douglas J. Lamont, Siraj Pallichankandy, Karthikeyan Subburayan, Ameer Alakkal, Rachid Rezgui, Alex Gray, D. Grahame Hardie, Sehamuddin Galadari (Lead / Corresponding author)

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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.

Original languageEnglish
Article number110761
Number of pages18
JournalCell Reports
Volume39
Issue number5
DOIs
Publication statusPublished - 3 May 2022

Keywords

  • AMPK
  • anti-Fas
  • apoptosis
  • caspase
  • catalytic
  • cl-AMPK-α1
  • cleavage
  • CP: Cell biology
  • CP: Molecular biology
  • etoposide
  • kinase
  • nuclear export sequence

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