Caspase cleavage and nuclear retention of the energy sensor AMPK-a1 during apoptosis

被引：20

作者：

Cheratta, Anees Rahman ^{[1
]}

Thayyullathil, Faisal ^{[1
]}

Hawley, Simon A. ^{[3
]}

Ross, Fiona A. ^{[3
]}

Atrih, Abdelmajdid ^{[4
]}

Lamont, Douglas J. ^{[4
]}

Pallichankandy, Siraj ^{[1
]}

Subburayan, Karthikeyan ^{[1
]}

Alakkal, Ameer ^{[1
]}

Rezgui, Rachid ^{[2
]}

Gray, Alex ^{[3
]}

Hardie, D. Grahame ^{[3
]}

Galadari, Sehamuddin ^{[1
]}

机构：

[1] New York Univ Abu Dhabi, Div Sci, Cell Death Signaling Lab, Expt Res Bldg,POB 129188, Abu Dhabi, U Arab Emirates

[2] New York Univ Abu Dhabi, Core Technol Platform, Expt Res Bldg,POB 129188, Abu Dhabi, U Arab Emirates

[3] Univ Dundee, Sch Life Sci, Div Cell Signalling & Immunol, Dundee DD1 5EH, Scotland

[4] Univ Dundee, Sch Life Sci, Fingerprints Prote Facil, Dundee DD1 5EH, Scotland

来源：

CELL REPORTS | 2022年 / 39卷 / 05期

基金：

英国惠康基金; 芬兰科学院;

关键词：

ACTIVATED PROTEIN-KINASE; SKELETAL-MUSCLE; CELL-DEATH; RAT-LIVER; PHOSPHORYLATION; IDENTIFICATION; TRANSCRIPTION; LOCALIZATION; ISOFORMS; SUBUNIT;

D O I：

10.1016/j.celrep.2022.110761

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

AMP-activated protein kinase (AMPK) coordinates energy homeostasis during metabolic and energy stress. We report that the catalytic subunit isoform AMPK-a1 (but not a2) is cleaved by caspase-3 at an early stage during induction of apoptosis. AMPK-a1 cleavage occurs following Asp529, generating an-58-kDa N-terminal fragment (cl-AMPK-a1) 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-a1 to become phosphorylated and activated by the upstream kinases LKB1 or CaMKK2, or (3) allosteric activation by AMP or A-769662. Importantly, cl-AMPK-a1 is only detectable in the nucleus, consistent with removal of the NES, and ectopic expression of cleavage-resistant D529A-mutant AMPK-a1 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.

引用

页数：18

共 39 条

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