TY - JOUR
T1 - Caspase cleavage and nuclear retention of the energy sensor AMPK-α1 during apoptosis
AU - Cheratta, Anees Rahman
AU - Thayyullathil, Faisal
AU - Hawley, Simon A.
AU - Ross, Fiona A.
AU - Atrih, Abdelmajdid
AU - Lamont, Douglas J.
AU - Pallichankandy, Siraj
AU - Subburayan, Karthikeyan
AU - Alakkal, Ameer
AU - Rezgui, Rachid
AU - Gray, Alex
AU - Hardie, D. Grahame
AU - Galadari, Sehamuddin
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/5/3
Y1 - 2022/5/3
N2 - 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.
AB - 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.
KW - AMPK
KW - CP: Cell biology
KW - CP: Molecular biology
KW - anti-Fas
KW - apoptosis
KW - caspase
KW - catalytic
KW - cl-AMPK-α1
KW - cleavage
KW - etoposide
KW - kinase
KW - nuclear export sequence
UR - https://www.scopus.com/pages/publications/85129415194
UR - https://www.scopus.com/pages/publications/85129415194#tab=citedBy
U2 - 10.1016/j.celrep.2022.110761
DO - 10.1016/j.celrep.2022.110761
M3 - Article
C2 - 35508122
AN - SCOPUS:85129415194
SN - 2211-1247
VL - 39
JO - Cell Reports
JF - Cell Reports
IS - 5
M1 - 110761
ER -