Cell Death Signaling Laboratory (Division of Science), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island, Abu Dhabi, UAE.
Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, Scotland DD1 5EH, UK.
Cell Rep. 2022 May 3;39(5):110761. doi: 10.1016/j.celrep.2022.110761.
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.
AMP 激活的蛋白激酶 (AMPK) 在代谢和能量应激过程中协调能量稳态。我们报告说，在细胞凋亡诱导的早期阶段， caspase-3 会切割催化亚基同工型 AMPK-α1（但不是 α2）。AMPK-α1 的切割发生在 Asp529 之后，产生一个约 58kDa 的 N 端片段（cl-AMPK-α1），并导致核输出序列（NES）从 C 端精确切除。这种切割不会影响（1）预形成的异三聚体复合物的稳定性，（2）cl-AMPK-α1 被上游激酶 LKB1 或 CaMKK2 磷酸化和激活的能力，或（3）由 AMP 或 A-769662 引起的变构激活。重要的是，cl-AMPK-α1 仅在细胞核中检测到，与 NES 的去除一致，并且异位表达切割抗性 D529A 突变 AMPK-α1 可促进细胞死亡诱导的细胞毒性剂。因此，我们阐明了细胞核内 AMPK 激活的一种非经典机制，该机制可保护细胞免受 DNA 损伤诱导的死亡。
