DNA-dependent protein kinase regulates lysosomal AMP-dependent protein kinase activation and autophagy
Journal article
Puustinen, Pietri, Keldsbo, Anne, Corcelle-Termeau, Elisabeth, Ngoei, Kevin, Sønder, Stine L., Farkas, Thomas, Kaae Andersen, Klaus, Oakhill, Jon S. and Jäättelä, Marja. (2020). DNA-dependent protein kinase regulates lysosomal AMP-dependent protein kinase activation and autophagy. Autophagy. 16(10), pp. 1871-1888. https://doi.org/10.1080/15548627.2019.1710430
Authors | Puustinen, Pietri, Keldsbo, Anne, Corcelle-Termeau, Elisabeth, Ngoei, Kevin, Sønder, Stine L., Farkas, Thomas, Kaae Andersen, Klaus, Oakhill, Jon S. and Jäättelä, Marja |
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Abstract | Macroautophagy/autophagy is a central component of the cytoprotective cellular stress response. To enlighten stress-induced autophagy signaling, we screened a human kinome siRNA library for regulators of autophagic flux in MCF7 human breast carcinoma cells and identified the catalytic subunit of DNA-dependent protein kinase PRKDC/DNA-PKcs as a positive regulator of basal and DNA damage-induced autophagy. Analysis of autophagy-regulating signaling cascades placed PRKDC upstream of the AMP-dependent protein kinase (AMPK) complex and ULK1 kinase. In normal culture conditions, PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity. Instead, the disturbance of PRKDC-mediated phosphorylation of PRKAG1 inhibited the lysosomal localization of the AMPK complex and its starvation-induced association with STK11 (serine/threonine kinase 11). Taken together, our data suggest that PRKDC-mediated phosphorylation of PRKAG1 primes AMPK complex to the lysosomal activation by STK11 in cancer cells thereby linking DNA damage response to autophagy and cellular metabolism. |
Keywords | AMPK; autophagy; lysosome; metabolism; PRKDC; signaling |
Year | 2020 |
Journal | Autophagy |
Journal citation | 16 (10), pp. 1871-1888 |
Publisher | Taylor & Francis |
ISSN | 1554-8627 |
Digital Object Identifier (DOI) | https://doi.org/10.1080/15548627.2019.1710430 |
Scopus EID | 2-s2.0-85078418390 |
Research or scholarly | Research |
Page range | 1871-1888 |
Funder | National Health and Medical Research Council (NHMRC) |
Australian Research Council (ARC) | |
Publisher's version | License All rights reserved File Access Level Controlled |
Output status | Published |
Publication dates | |
Online | 26 Jan 2020 |
Publication process dates | |
Accepted | 26 Dec 2019 |
Deposited | 14 May 2021 |
https://acuresearchbank.acu.edu.au/item/8w0x7/dna-dependent-protein-kinase-regulates-lysosomal-amp-dependent-protein-kinase-activation-and-autophagy
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