The association of AMPK with ULK1 regulates autophagy
- PMID: 21072212
- PMCID: PMC2972217
- DOI: 10.1371/journal.pone.0015394
The association of AMPK with ULK1 regulates autophagy
Abstract
Autophagy is a highly orchestrated intracellular bulk degradation process that is activated by various environmental stresses. The serine/threonine kinase ULK1, like its yeast homologue Atg1, is a key initiator of autophagy that is negatively regulated by the mTOR kinase. However, the molecular mechanism that controls the inhibitory effect of mTOR on ULK1-mediated autophagy is not fully understood. Here we identified AMPK, a central energy sensor, as a new ULK1-binding partner. We found that AMPK binds to the PS domain of ULK1 and this interaction is required for ULK1-mediated autophagy. Interestingly, activation of AMPK by AICAR induces 14-3-3 binding to the AMPK-ULK1-mTORC1 complex, which coincides with raptor Ser792 phosphorylation and mTOR inactivation. Consistently, AICAR induces autophagy in TSC2-deficient cells expressing wild-type raptor but not the mutant raptor that lacks the AMPK phosphorylation sites (Ser722 and Ser792). Taken together, these results suggest that AMPK association with ULK1 plays an important role in autophagy induction, at least in part, by phosphorylation of raptor to lift the inhibitory effect of mTOR on the ULK1 autophagic complex.
Conflict of interest statement
Figures
Similar articles
-
ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding.Autophagy. 2011 Jul;7(7):737-47. doi: 10.4161/auto.7.7.15491. Epub 2011 Jul 1. Autophagy. 2011. PMID: 21460630 Free PMC article.
-
Alcohol and PRAS40 knockdown decrease mTOR activity and protein synthesis via AMPK signaling and changes in mTORC1 interaction.J Cell Biochem. 2010 Apr 15;109(6):1172-84. doi: 10.1002/jcb.22496. J Cell Biochem. 2010. PMID: 20127721 Free PMC article.
-
LKB1 and AMP-activated protein kinase control of mTOR signalling and growth.Acta Physiol (Oxf). 2009 May;196(1):65-80. doi: 10.1111/j.1748-1716.2009.01972.x. Epub 2009 Feb 19. Acta Physiol (Oxf). 2009. PMID: 19245654 Free PMC article. Review.
-
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.Nat Cell Biol. 2011 Feb;13(2):132-41. doi: 10.1038/ncb2152. Epub 2011 Jan 23. Nat Cell Biol. 2011. PMID: 21258367 Free PMC article.
-
The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis.Biochem Soc Trans. 2013 Aug;41(4):939-43. doi: 10.1042/BST20130030. Biochem Soc Trans. 2013. PMID: 23863160 Review.
Cited by
-
The interplay between autophagy and cGAS-STING signaling and its implications for cancer.Front Immunol. 2024 Apr 10;15:1356369. doi: 10.3389/fimmu.2024.1356369. eCollection 2024. Front Immunol. 2024. PMID: 38660307 Free PMC article. Review.
-
LEDT and Idebenone treatment modulate autophagy and improve regenerative capacity in the dystrophic muscle through an AMPK-pathway.PLoS One. 2024 Mar 18;19(3):e0300006. doi: 10.1371/journal.pone.0300006. eCollection 2024. PLoS One. 2024. PMID: 38498472 Free PMC article.
-
The potential of herbal drugs to treat heart failure: The roles of Sirt1/AMPK.J Pharm Anal. 2024 Feb;14(2):157-176. doi: 10.1016/j.jpha.2023.09.001. Epub 2023 Sep 27. J Pharm Anal. 2024. PMID: 38464786 Free PMC article. Review.
-
14-3-3 proteins-a moonlight protein complex with therapeutic potential in neurological disorder: in-depth review with Alzheimer's disease.Front Mol Biosci. 2024 Feb 5;11:1286536. doi: 10.3389/fmolb.2024.1286536. eCollection 2024. Front Mol Biosci. 2024. PMID: 38375509 Free PMC article. Review.
-
Contrasting views on the role of AMPK in autophagy.Bioessays. 2024 Mar;46(3):e2300211. doi: 10.1002/bies.202300211. Epub 2024 Jan 12. Bioessays. 2024. PMID: 38214366
References
-
- Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol. 2009;10:458–467. - PubMed
-
- Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–484. - PubMed
-
- Mizushima N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 2010 - PubMed
-
- Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol. 2007;9:316–323. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous