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
Affiliations
Anees Rahman Cheratta
Cell Death Signaling Laboratory (Division of Science), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island, Abu Dhabi, UAE
Faisal Thayyullathil
Cell Death Signaling Laboratory (Division of Science), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island, Abu Dhabi, UAE
Simon A. Hawley
Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland DD1 5EH, UK
Fiona A. Ross
Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland DD1 5EH, UK
Abdelmajdid Atrih
Fingerprints Proteomics Facility, School of Life Sciences, University of Dundee, Dundee, Scotland DD1 5EH, UK
Douglas J. Lamont
Fingerprints Proteomics Facility, School of Life Sciences, University of Dundee, Dundee, Scotland DD1 5EH, UK
Siraj Pallichankandy
Cell Death Signaling Laboratory (Division of Science), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island, Abu Dhabi, UAE
Karthikeyan Subburayan
Cell Death Signaling Laboratory (Division of Science), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island, Abu Dhabi, UAE
Ameer Alakkal
Cell Death Signaling Laboratory (Division of Science), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island, Abu Dhabi, UAE
Rachid Rezgui
Core Technology Platform, Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island, Abu Dhabi, UAE
Alex Gray
Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland DD1 5EH, UK
D. Grahame Hardie
Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland DD1 5EH, UK; Corresponding author
Sehamuddin Galadari
Cell Death Signaling Laboratory (Division of Science), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island, Abu Dhabi, UAE; Corresponding author
Summary: 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.
