AMPK regulates autophagy by phosphorylating BECN1 at threonine 388

Zhang, Deyi; Wang, Wei; Sun, Xiujie; Xu, Daqian; Wang, Chenyao; Zhang, Qian; Wang, Huafei; Luo, Wenwen; Chen, Yan; Chen, Huaiyong; Liu, Zhixue

doi:10.1080/15548627.2016.1185576

Cited by 175 publications

(139 citation statements)

References 42 publications

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“…AMPK directly phosphorylates BECN1 at serines 91 and 94 and is required for stable ATG14 interactions for the proautophagy activation of the BECN1 complex (66). Similar results were found for HEK-293T cells (67). Cells that were treated with AICAR, an AMPK activator, induced autophagic signals, as measured by LC3 lipidation and LC3 punctum quantification, to the same extent as glucose starvation.…”

Section: Ulk1/2-independent Autophagy Induction Ulk1/2-independent Ausupporting

confidence: 73%

So Many Roads: the Multifaceted Regulation of Autophagy Induction

Velazquez

Jackson

2018

Molecular and Cellular Biology

102

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Autophagy is an evolutionary conserved, degradative process from single-cell eukaryotes, such as , to higher mammals, such as humans. The regulation of autophagy has been elucidated through the combined study of yeast,, mice, , and humans. MTOR, the major negative regulator of autophagy, and activating nutrient kinases, such as 5'-AMP-activated protein kinase (AMPK), interact with the autophagy regulatory complex: ULK1/2, RB1CC1, ATG13, and ATG101. The ULK1/2 complex induces autophagy by phosphorylating downstream autophagy complexes, such as the BECN1 PIK3 signaling complex that leads to the creation of LC3 autophagosomes. We highlight in this review various reports of autophagy induction that are independent of these regulators. We discuss reports of MTOR-independent, AMPK-independent, ULK1/2-independent, and BECN1-PIK3C3-independent autophagy. We illustrate that autophagy induction and the components required vary by the nature of the induction signal and type of cell and do not always require canonical members of the autophagy signaling pathway. We illustrate that rather than thinking of autophagy as a linear pathway, it is better to think of autophagy induction as an interconnecting web of key regulators, many of which can induce autophagy through different requirements depending on the type and length of induction signals.

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Section: Ulk1/2-independent Autophagy Induction Ulk1/2-independent Ausupporting

confidence: 73%

So Many Roads: the Multifaceted Regulation of Autophagy Induction

Velazquez

Jackson

2018

Molecular and Cellular Biology

102

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“…53 Beclin 1 is the major regulator node between them by directly binding Bcl-2 to suppress autophagy, 54 whereas it dissociates from Bcl-2 to activate autophagy when phosphorylated by AMPK. 55 Consistently, HY-SDT induced the time-dependent increase of autophagy as well as p-AMPK and Beclin 1 reversed by AMPK inhibitor CC. Meanwhile, the released Beclin 1 is also reported to trigger apoptosis when translocating to the outer mitochondrial membrane.…”

Section: Discussionmentioning

confidence: 73%

Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB

Zhang

Zheng

et al. 2016

Cell Death Dis

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Lipid catabolism disorder is the primary cause of atherosclerosis. Transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy to promote lipid degradation. Hypericin-mediated sonodynamic therapy (HY-SDT) has been proved non-invasively inducing THP-1-derived macrophage apoptosis; however, it is unknown whether macrophage autophagy could be triggered by HY-SDT to influence cellular lipid catabolism via regulating TFEB. Here, we report that HY-SDT resulted in the time-dependent THP-1-derived macrophage autophagy activation through AMPK/AKT/mTOR pathway. Besides, TFEB nuclear translocation in macrophage was triggered by HY-SDT to promote autophagy activation and lysosome regeneration which enhanced lipid degradation in response to atherogenic lipid stressors. Moreover, following HY-SDT, the ABCA1 expression level was increased to promote lipid efflux in macrophage, and the expression levels of CD36 and SR-A were decreased to inhibit lipid uptake, both of which were prevented by TFEB knockdown. These results indicated that TFEB nuclear translocation activated by HY-SDT was not only the key regulator of autophagy activation and lysosome regeneration in macrophage to promote lipolysis, but also had a crucial role in reverse cholesterol transporters to decrease lipid uptake and increase lipid efflux. Reactive oxygen species (ROS) were adequately generated in macrophage by HY-SDT. Further, ROS scavenger N-acetyl-l-cysteine abolished HY-SDT-induced TFEB nuclear translocation and autophagy activation, implying that ROS were the primary upstream factors responsible for these effects during HY-SDT. In summary, our data indicate that HY-SDT decreases lipid content in macrophage by promoting ROS-dependent nuclear translocation of TFEB to influence consequent autophagy activation and cholesterol transporters. Thus, HY-SDT may be beneficial for atherosclerosis via TFEB regulation to ameliorate lipid overload in atherosclerotic plaques.

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“…180), Thr133 and Ser135 on VPS34 (REF. 181), Ser91 and Ser94 on Beclin1 (REFS 181,182), Thr50 on the VPS34-associated protein RACK1 (REF. 183) and Thr32 on PAQR3, an ATG14L–VPS34 scaffolding protein 184 .…”

Section: Ampk Regulates Autophagy and Mitophagymentioning

confidence: 99%

AMPK: guardian of metabolism and mitochondrial homeostasis

Herzig

Shaw

2017

Nat Rev Mol Cell Biol

2,750

2,008

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Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability. Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex. Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption. In the past decade, the discovery of numerous new AMPK substrates has led to a more complete understanding of the minimal number of steps required to reprogramme cellular metabolism from anabolism to catabolism. This energy switch controls cell growth and several other cellular processes, including lipid and glucose metabolism and autophagy. Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy This Review discusses how AMPK functions as a central mediator of the cellular response to energetic stress and mitochondrial insults and coordinates multiple features of autophagy and mitochondrial biology.

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AMPK regulates autophagy by phosphorylating BECN1 at threonine 388

Cited by 175 publications

References 42 publications

So Many Roads: the Multifaceted Regulation of Autophagy Induction

So Many Roads: the Multifaceted Regulation of Autophagy Induction

Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB

AMPK: guardian of metabolism and mitochondrial homeostasis

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