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

doi:10.1016/j.celrep.2022.110761

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 language	English
Article number	110761
Number of pages	18
Journal	Cell Reports
Volume	39
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2022.110761
Publication status	Published - 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

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.celrep.2022.110761Licence: CC BY

Final published versionFinal published version, 2.75 MBLicence: CC BY

Cite this

@article{47801472722c42d8805eb955fa22dba9,

title = "Caspase cleavage and nuclear retention of the energy sensor AMPK-α1 during apoptosis",

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.",

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

author = "Cheratta, {Anees Rahman} and Faisal Thayyullathil and Hawley, {Simon A.} and Ross, {Fiona A.} and Abdelmajdid Atrih and Lamont, {Douglas J.} and Siraj Pallichankandy and Karthikeyan Subburayan and Ameer Alakkal and Rachid Rezgui and Alex Gray and Hardie, {D. Grahame} and Sehamuddin Galadari",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors. Published by Elsevier Inc. All rights reserved. This work was financially supported by grants from New York University Abu Dhabi Research Enhancement Fund (RE252) to S.G. We also acknowledge the NYUAD Core Technology Platform for their support. D.G.H. was supported by a Wellcome Trust Investigator Award (204766). ",

year = "2022",

month = may,

day = "3",

doi = "10.1016/j.celrep.2022.110761",

language = "English",

volume = "39",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier",

number = "5",

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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: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. This work was financially supported by grants from New York University Abu Dhabi Research Enhancement Fund (RE252) to S.G. We also acknowledge the NYUAD Core Technology Platform for their support. D.G.H. was supported by a Wellcome Trust Investigator Award (204766).

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 - anti-Fas

KW - apoptosis

KW - caspase

KW - catalytic

KW - cl-AMPK-α1

KW - cleavage

KW - CP: Cell biology

KW - CP: Molecular biology

KW - etoposide

KW - kinase

KW - nuclear export sequence

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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 -

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

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Role of AMPK in Nutrient Sensing and in Cancer (Investigator Award Renewal)

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

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