So Many Roads: the Multifaceted Regulation of Autophagy Induction

Velazquez, Angel F. Corona; Jackson, William T.

doi:10.1128/mcb.00303-18

Cited by 102 publications

(90 citation statements)

References 88 publications

(103 reference statements)

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“…AMPK phosphorylates and controls important upstream regulators of the autophagic cascade, including the ULK1 and the VPS34-dependent PI3K complexes that govern initial steps in the formation of phagophores giving rise to autophagosomes [9][10][11] . However, the molecular mechanisms of autophagy regulation are not fully resolved and may not be linear 40 . With Cyclin Y/CDK16 we have identified an additional effector of AMPK.…”

Section: Articlementioning

confidence: 99%

AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy

et al. 2020

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The AMP-activated protein kinase (AMPK) is a master sensor of the cellular energy status that is crucial for the adaptive response to limited energy availability. AMPK is implicated in the regulation of many cellular processes, including autophagy. However, the precise mechanisms by which AMPK controls these processes and the identities of relevant substrates are not fully understood. Using protein microarrays, we identify Cyclin Y as an AMPK substrate that is phosphorylated at Serine 326 (S326) both in vitro and in cells. Phosphorylation of Cyclin Y at S326 promotes its interaction with the Cyclin-dependent kinase 16 (CDK16), thereby stimulating its catalytic activity. When expressed in cells, Cyclin Y/CDK16 is sufficient to promote autophagy. Moreover, Cyclin Y/CDK16 is necessary for efficient AMPK-dependent activation of autophagy. This functional interaction is mediated by AMPK phosphorylating S326 of Cyclin Y. Collectively, we define Cyclin Y/CDK16 as downstream effector of AMPK for inducing autophagy.

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Section: Articlementioning

confidence: 99%

AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy

et al. 2020

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“…Phosphorylation on Ser750 residue of ULK2 by SGK1 (as its authentic substrate protein) is also one of regulatory points to activate its autophagy functions. It has been reported that mTOR1 phosphorylation on Ser729 in (kavlftvgSpphs) of ULK2 also enhances ULK2's autophagy activity [1] [2] [3] [4].…”

Section: Discussionmentioning

confidence: 99%

“…Uncoordinated 51-like kinase 2 (ULK2), like ULK1, is a member of the serine/threonine kinase protein family that plays an essential role in the regulation American Journal of Molecular Biology of autophagy in mammalian cells. ULK2 is expressed ubiquitously [1] [2] [3] [4].…”

Section: Introductionmentioning

confidence: 99%

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SGK1 Inhibits ULK2 Autophagy Activity

Sein¹,

Lee²,

Hyun³

et al. 2020

AJMB

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Serum-and glucocorticoid-induced kinase 1 (SGK1) is known to have consensus sequence of phosphorylation site R-x-R-x-x-(S/T)-Φ, where Φ is any hydrophobic amino acid and arginine residues are conserved at positions −5 and −3 relative to positions of Ser/Thr residues that are phosphorylated in the presence of SGK1. UNC-21-like kinase 2 (ULK2) also harbors putative SGK1 phosphorylation sites at both Ser507 (502 RsRnsSG 508) and Ser750 (745 RtRttSV 751) residues. Thus, the objective of this study was to determine whether Ser507 and Ser750 residues of ULK2 could be phosphorylation sites of SGK1 as one of its authentic substrate proteins. Using ULK2 507 and 750 serine residue un-or phosphorylation analog (S507AS750A or 507DS750D), we observed that modification of Ser507 or Ser750 residue was required to activate the kinase activity of ULK2 and sensitize ULK2 to stress or starvation while simultaneously enhancing its active state and autophagy characteristics, suggesting that phosphorylation at Ser750 or Ser507 residue could modulate its subcellular localization and protein interaction with AMPK1α to activate ULK2. We also observed that ULK2 autophagy activity was enhanced by GSK650394 (an SGK1 inhibitor) to compensate survival capacity through increasing its association with LC3 and phosphorylation. When SGK1 known to be associated with cell survival was inhibited by GSK650394, ULK2 autophagy pathway was activated to avoid cell death alternatively. Thus, our observations indicate that phosphorylation of ULK2 by SGK1 can regulate cell survival as an alternative modulation of ULK2 functions.

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“…The mammalian target of rapamycin (mTor) kinase is an important regulator of autophagy induction where active mTOR suppresses autophagy while inhibition of mTOR activity promotes autophagy onset (Rabinowitz and White, 2010), although a growing number of examples of mTOR-independent autophagy induction have been reported providing the notion that autophagy induction is not a single linear process but can rather be induced through the action of multiple interconnected key regulators (Corona Velazquez and Jackson, 2018). While autophagy is largely a cytoplasmic event, recent studies have focussed on the nuclear transcription factors and epigenetic marks that modulate the expression of various autophagic components (reviewed in Fullgrabe et al (2014)).…”

Section: Introductionmentioning

confidence: 99%

Human ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy regulation

Barthez

Poplineau

Elrefaey

et al. 2019

Preprint

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Autophagy is an essential cellular process that maintains homeostasis by recycling damaged organelles and nutrients during development and cellular stress. ZKSCAN3 is the sole identified master transcriptional repressor of autophagy in humans. How ZKSCAN3 achieves autophagy repression at the mechanistic or organismal level however still remains to be elucidated. Here, we demonstrate that vertebrate ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy repression. Expression of ZKSCAN3 in Drosophila prevents premature autophagy onset due to loss of M1BP function and conversely, M1BP expression in human cells can prevent starvation-induced autophagy due to loss of nuclear ZKSCAN3 function. In Drosophila ZKSCAN3 binds genome-wide to sequences targeted by M1BP and transcriptionally regulates the majority of M1BP-controlled genes. These data allow the potential for transitioning the mechanisms, gene targets and plethora metabolic processes controlled by M1BP onto ZKSCAN3 and opens up Drosophila as a tool in studying the function of ZKSCAN3 in autophagy and tumourigenesis.

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So Many Roads: the Multifaceted Regulation of Autophagy Induction

Cited by 102 publications

References 88 publications

AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy

AMPK-dependent activation of the Cyclin Y/CDK16 complex controls autophagy

SGK1 Inhibits ULK2 Autophagy Activity

Human ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy regulation

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