Regulation of nutrient-sensitive autophagy by uncoordinated 51-like kinases 1 and 2

McAlpine, Fiona E; Williamson, Leon E.; Tooze, Sharon A.; Chan, Edmond Y W

doi:10.4161/auto.23066

Cited by 133 publications

(150 citation statements)

References 48 publications

(87 reference statements)

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“…18,19 Using siRNA-mediated knockdown of genes encoding ULK complex components including ULK1, ATG13 and RB1CC1 as well as siRNA-targeting the gene for the autophagy receptor protein SQSTM1, we confirmed that all 3 ULK complex components have a comparable effect on basal autophagic flux (Fig. 6A, Fig.…”

Section: Ulk1 Is Required For Basal Autophagy and Autophagic Flux Undsupporting

confidence: 50%

Suppressed translation and ULK1 degradation as potential mechanisms of autophagy limitation under prolonged starvation

Allavena

Boyd

et al. 2016

Autophagy

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Macroautophagy/autophagy is a well-organized process of intracellular degradation, which is rapidly activated under starvation conditions. Recent data demonstrate a transcriptional upregulation of several autophagy genes as a mechanism that controls autophagy in response to starvation. Here we report that despite the significant upregulation of mRNA of the essential autophagy initiation gene ULK1, its protein level is rapidly reduced under starvation. Although both autophagic and proteasomal systems contribute to the degradation of ULK1, under prolonged nitrogen deprivation, its level was still reduced in ATG7 knockout cells, and only initially stabilized in cells treated with the lysosomal or proteasomal inhibitors. We demonstrate that under starvation, protein translation is rapidly diminished and, similar to treatments with the proteosynthesis inhibitors cycloheximide or anisomycin, is associated with a significant reduction of ULK1. Furthermore, it was found that inhibition of the mitochondrial respiratory complexes or the mitochondrial ATP synthase function that could also take place in the absence of substrates, promote upregulation of ULK1 mRNA and protein expression in an AMPK-dependent manner in U1810 lung cancer cells growing in complete culture medium. These inhibitors could also drastically increase the ULK1 protein in U1810 cells with knockout of ATG13, where the ULK1 expression is significantly diminished. However, such upregulation of ULK1 protein is negligible under starvation conditions, further signifying the contribution of translation and suggesting that transcriptional upregulation of ULK1 protein will be diminished under such conditions. Thus, we propose a model where inhibition of protein translation, together with the degradation systems, limit autophagy during starvation.

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Section: Ulk1 Is Required For Basal Autophagy and Autophagic Flux Undsupporting

confidence: 50%

Suppressed translation and ULK1 degradation as potential mechanisms of autophagy limitation under prolonged starvation

Allavena

Boyd

et al. 2016

Autophagy

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“…Accordingly, although WIPI1 localization at autophagosomal membranes is ablated upon Ca 2+ chelation, WIPI1-positive autophagosomes are formed in AMPK-deficient mouse embryonic fibroblasts, probably involving an AMPK-independent route through CAMKI (Pfisterer et al, 2011). It is noteworthy that the PtdIns3P effector function of WIPI1 does not respond to glucose starvation (McAlpine et al, 2013;Pfisterer et al, 2011), which generally activates AMPK. Glucose starvation has been suggested to signal independently of PtdIns3P to trigger autophagy (McAlpine et al, 2013).…”

Section: Wipi1mentioning

confidence: 97%

“…It has been demonstrated that mTORC1 inhibition, either by rapamycin administration (Proikas-Cezanne et al, 2007), siRNAmediated mTOR downregulation (Gaugel et al, 2012) or FOXOmediated glutamine production (van der Vos et al, 2012), promotes the localization of WIPI1 at the nascent autophagosome. This specific localization of WIPI1 is counteracted by the downregulation of ULK1 or PI3KC3 (Itakura and Mizushima, 2010;McAlpine et al, 2013). Hence, the activation of ULK1 and PI3KC3, followed by localized PtdIns3P production, rapidly attracts WIPI1 through its PtdIns3P-binding specificity.…”

Section: Wipi1mentioning

confidence: 99%

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WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome

Proikas‐Cezanne

Takacs

Dönnes

et al. 2015

Journal of Cell Science

240

236

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Autophagy is a pivotal cytoprotective process that secures cellular homeostasis, fulfills essential roles in development, immunity and defence against pathogens, and determines the lifespan of eukaryotic organisms. However, autophagy also crucially contributes to the development of age-related human pathologies, including cancer and neurodegeneration. Macroautophagy (hereafter referred to as autophagy) clears the cytoplasm by stochastic or specific cargo recognition and destruction, and is initiated and executed by autophagy related (ATG) proteins functioning in dynamical hierarchies to form autophagosomes. Autophagosomes sequester cytoplasmic cargo material, including proteins, lipids and organelles, and acquire acidic hydrolases from the lysosomal compartment for cargo degradation. Prerequisite and essential for autophagosome formation is the production of phosphatidylinositol 3-phosphate (PtdIns3P) by phosphatidylinositol 3-kinase class III (PI3KC3, also known as PIK3C3) in complex with beclin 1, p150 (also known as PIK3R4; Vps15 in yeast) and ATG14L. Members of the human WDrepeat protein interacting with phosphoinositides (WIPI) family play an important role in recognizing and decoding the PtdIns3P signal at the nascent autophagosome, and hence function as autophagy-specific PtdIns3P-binding effectors, similar to their ancestral yeast Atg18 homolog. The PtdIns3P effector function of human WIPI proteins appears to be compromised in cancer and neurodegeneration, and WIPI genes and proteins might present novel targets for rational therapies. Here, we summarize the current knowledge on the roles of the four human WIPI proteins, WIPI1-4, in autophagy.This article is part of a Focus on Autophagosome biogenesis. For further reading, please see related articles: 'ERES: sites for autophagosome biogenesis and maturation?' by Jana SanchezWandelmer et al. (J. Cell Sci. 128,(185)(186)(187)(188)(189)(190)(191)(192) and 'Membrane dynamics in autophagosome biogenesis' by Sven R. Carlsson and Anne Simonsen (J. Cell Sci. 128,(193)(194)(195)(196)(197)(198)(199)(200)(201)(202)(203)(204)(205).

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“…AMPK␣1 Ϫ/Ϫ AMPK␣2 Ϫ/Ϫ MEFs, which lack both isoforms of the genes that encode the catalytic ␣-subunit of AMPK, have been described previously and were kindly provided by Dr. Sara Cherry (U. Pennsylvania) (42,43). ULK1 ϩ/ϩ , ULK1 Ϫ/Ϫ , and ULK1 Ϫ/Ϫ ULK2 Ϫ/Ϫ MEFs were kindly provided by Dr. Sharon Tooze (44). MEFs were routinely cultured in DMEM containing 5% FBS.…”

Section: Primary Macrophage Isolation and In Vitro Cell Culture-mentioning

confidence: 99%

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

Prantner

Perkins

Vogel

2017

Journal of Biological Chemistry

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Edited by Luke O'NeillThe host protein Stimulator of Interferon Genes (STING) has been shown to be essential for recognition of both viral and intracellular bacterial pathogens, but its regulation remains unclear. Previously, we reported that mitochondrial membrane potential regulates STING-dependent IFN-␤ induction independently of ATP synthesis. Because mitochondrial membrane potential controls calcium homeostasis, and AMP-activated protein kinase (AMPK) is regulated, in part, by intracellular calcium, we postulated that AMPK participates in STING activation; however, its role has yet to be been defined. Addition of an intracellular calcium chelator or an AMPK inhibitor to either mouse macrophages or mouse embryonic fibroblasts (MEFs) suppressed IFN-␤ and TNF-␣ induction following stimulation with the STING-dependent ligand 5,6-dimethyl xanthnone-4-acetic acid (DMXAA). These pharmacological findings were corroborated by showing that MEFs lacking AMPK activity also failed to up-regulate IFN-␤ and TNF-␣ after treatment with DMXAA or the natural STING ligand cyclic GMP-AMP (cGAMP). As a result, AMPK-deficient MEFs exhibit impaired control of vesicular stomatitis virus (VSV), a virus sensed by STING that can cause an influenza-like illness in humans. This impairment could be overcome by pretreatment of AMPK-deficient MEFs with type I IFN, illustrating that de novo production of IFN-␤ in response to VSV plays a key role in antiviral defense during infection. Loss of AMPK also led to dephosphorylation at Ser-555 of the known STING regulator, UNC-51-like kinase 1 (ULK1). However, ULK1-deficient cells responded normally to DMXAA, indicating that AMPK promotes STING-dependent signaling independent of ULK1 in mouse cells.Pathogen sensing by innate immune cells is essential for host defense in response to invading microorganisms. Recognition by pattern recognition receptors typically activates signal transduction pathways, leading to up-regulation of cytokines like TNF-␣ and IFN-␤. Although IFN-␤ has a well established role in defense against viral infection, intracellular bacterial infections also induce this cytokine. In the past decade, our understanding of the molecular basis for these signaling pathways has expanded greatly and it has been discovered that there is some overlap between proteins responsible for recognition of bacteria and virus alike. One particular example is the mitochondrial and endoplasmic reticulum resident protein stimulator of interferon genes (STING) 2 (1-3). STING has been shown to be crucial for recognition of both DNA viruses (4 -6) and intracellular bacterial pathogens (7-12). STING senses DNA viruses indirectly, requiring the host enzyme cyclic GMP-AMP synthase (cGAS) to convert the viral double stranded DNA into the compound cGAMP (13-15). This metazoan second messenger, in turn, binds with high affinity to STING dimers, changing the protein conformation (16), such that it leads to activation of the kinase TBK1 and subsequent phosphorylation of the transcription factor IRF3, which is piv...

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Regulation of nutrient-sensitive autophagy by uncoordinated 51-like kinases 1 and 2

Cited by 133 publications

References 48 publications

Suppressed translation and ULK1 degradation as potential mechanisms of autophagy limitation under prolonged starvation

Suppressed translation and ULK1 degradation as potential mechanisms of autophagy limitation under prolonged starvation

WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome

AMP-activated Kinase (AMPK) Promotes Innate Immunity and Antiviral Defense through Modulation of Stimulator of Interferon Genes (STING) Signaling

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