The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR

Molecular and Cell Biology Laboratory, Dulbecco Center for Cancer Research, University of California at San Diego, La Jolla, USA.
Autophagy (Impact Factor: 11.75). 06/2011; 7(6):643-4. DOI: 10.4161/auto.7.6.15123
Source: PubMed


The serine/threonine kinase ULK1 is a mammalian homolog of Atg1, part of the Atg1 kinase complex, which is the most upstream component of the core autophagy machinery conserved from yeast to mammals. In budding yeast, activity of the Atg1 kinase complex is inhibited by TORC1 (target of rapamycin complex 1), but how the counterpart ULK1 complex in mammalian cells is regulated has been unknown. Our laboratories recently discovered that AMPK associates with, and directly phosphorylates, ULK1 on several sites and this modification is required for ULK1 activation after glucose deprivation. In contrast, when nutrients are plentiful, the mTORC1 complex phosphorylates ULK1, preventing its association and activation by AMPK. These studies have revealed a molecular mechanism of ULK1 regulation by nutrient signals via the actions of AMPK and mTORC1.

    • "Therefore, the impairment of Hsp90 induction in response to IAV infection in Atg7 -/-MEFs may also be related to inactivation of NF-κB signaling, consequently reducing viral RNA synthesis. The mTOR signaling pathway is known to negatively regulate autophagy (Egan et al., 2011). We previously reported that PGG induces autophagy by inhibiting the mTOR signaling pathway (Pei et al., 2011). "
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    ABSTRACT: Influenza A virus (IAV) infection triggers autophagosome formation, but inhibits the fusion of autophagosomes with lysosomes. However, the role of autophagy in IAV replication is still largely unclarified. In this study, we aim to reveal the role of autophagy in IAV replication and the molecular mechanisms underlying the regulation. By using autophagy-deficient (Atg7-/-) MEFs, we demonstrated that autophagy deficiency significantly reduced the levels of viral proteins, mRNA and genomic RNAs (vRNAs) without affecting viral entry. We further found that autophagy deficiency lead to a transient increase in phosphorylation of mTOR and its downstream targets including 4E-BP1 and S6 at a very early stage of IAV infection, and markedly suppressed p70S6K phosphorylation at the late stage of IAV infection. Furthermore, autophagy deficiency resulted in impairment of Hsp90 induction in response to IAV infection. These results indicate that IAV regulates autophagy to benefit the accumulation of viral elements (synthesis of viral proteins and genomic RNA) during IAV replication. This regulation is associated with modulation of Hsp90 induction and mTOR/p70S6K signaling pathway. Our results provide important evidence for the role of autophagy in IAV replication and the mechanisms underlying the regulation.
    No preview · Article · Jan 2016 · The international journal of biochemistry & cell biology
    • "mTORC1 regulates numerous processes involved in cell growth and metabolism via the control of ribosomal biogenesis and translation, mediated by substrates that include S6K1 and 4E-BP1 (Laplante and Sabatini 2012). More recently, phosphoproteomic approaches have identifi ed new mTORC1 substrates with key roles in the regulation of insulin signaling, translation, and autophagy, including Grb10, Larp1, Patl1, and Ulk1 (Egan et al. 2011 ;Hsu et al . 2011 ;Kang et al . "
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    ABSTRACT: Lipids are essential for many cellular and organismal processes, yet an excess of lipids can cause toxicity. The liver is a key organ for the maintenance of lipid homeostasis, performing lipogenesis as well as mediating the exchange of lipoproteins with peripheral tissues. In this chapter, we focus primarily on the regulation of lipogenesis in the liver by the protein kinase mTOR (mechanistic Target of Rapamycin), a central sensor of environmental cues that coordinates growth, protein synthesis and metabolism with nutrient availability. The mTOR protein kinase is found in two distinct complexes, each of which plays a role in the regulation of lipogenesis. We discuss the regulation of lipogenesis both directly by hepatic mTOR, indirectly by mTOR in other organs, and the regulation of hepatic lipogenesis by hormones and growth factors that regulate mTOR. This regulation by mTOR is an extremely complex process that we are only now beginning to fully understand.
    No preview · Chapter · Jan 2016
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    • "Adjuvant potential of AMPK activators and nicotinamide riboside A feasible alternative strategy for boosting cerebral autophagy is to administer brain-permeable activators of AMP-activated kinase (AMPK); this enzyme activates autophagy by inhibiting mTORC1 activation while conferring an activating phosphorylation on ULK1 [87] [111] [112]. The currently available agents metformin and berberine, both employed in the management of diabetes, appear to have potential in this regard [113] [114] [115] [116] [117] [118]; resveratrol, which likewise activates AMPK in rodents, has been shown to increase cerebral autophagy in mice, thereby suppress extracellular accumulation of amyloid-beta, and also is beneficial in a rotenone-induced Parkinsonian syndrome [94] [101] [119]. "
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    ABSTRACT: Ketogenic diets are markedly neuroprotective, but the basis of this effect is still poorly understood. Recent studies demonstrate that ketone bodies increase neuronal levels of hypoxia-inducible factor-1α (HIF-1α), possibly owing to succinate-mediated inhibition of prolyl hydroxylase activity. Moreover, there is reason to suspect that ketones can activate Sirt1 in neurons, in part by increasing cytoplasmic and nuclear levels of Sirt1's obligate cofactor NAD(+). Another recent study has observed reduced activity of mTORC1 in the hippocampus of rats fed a ketogenic diet - an effect plausibly attributable to Sirt1 activation. Increased activities of HIF-1 and Sirt1, and a decrease in mTORC1 activity, could be expected to collaborate in the induction of neuronal macroautophagy. Considerable evidence points to moderate up-regulation of neuronal autophagy as a rational strategy for prevention of neurodegenerative disorders; elimination of damaged mitochondria that overproduce superoxide, as well as clearance of protein aggregates that mediate neurodegeneration, presumably contribute to this protection. Hence, autophagy may mediate some of the neuroprotective benefits of ketogenic diets. Brain-permeable agents which activate AMP-activated kinase, such as metformin and berberine, as well as the Sirt1 activator nicotinamide riboside, can also boost neuronal autophagy, and may have potential for amplifying the impact of ketogenesis on this process. Since it might not be practical for most people to adhere to ketogenic diets continuously, alternative strategies are needed to harness the brain-protective potential of ketone bodies. These may include ingestion of medium-chain triglycerides or coconut oil, intermittent ketogenic dieting, and possibly the use of supplements that promote hepatic ketogenesis - notably carnitine and hydroxycitrate - in conjunction with dietary regimens characterized by long daily episodes of fasting or carbohydrate avoidance.
    Full-text · Article · Aug 2015 · Medical Hypotheses
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