AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation

Shang, Libin; Wang, Xiaodong

doi:10.4161/auto.7.8.15860

Cited by 172 publications

(146 citation statements)

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“…As a regulator of autophagy (Kim et al., 2013; Mack, Zheng, Asara & Thomas, 2014; Shang & Wang, 2011), AMPK phosphorylation was found to be reduced in microglial cells after LPS exposure. Furthermore, the increase in AMPKα2 expression and reduction in p‐AMPK protein were restrained by the PPARγ antagonist T0070907 (Figure 3a,b).…”

Section: Resultsmentioning

confidence: 96%

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

et al. 2018

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SummaryMicroglia‐mediated neuroinflammation plays a dual role in various brain diseases due to distinct microglial phenotypes, including deleterious M1 and neuroprotective M2. There is growing evidence that the peroxisome proliferator‐activated receptor γ (PPARγ) agonist rosiglitazone prevents lipopolysaccharide (LPS)‐induced microglial activation. Here, we observed that antagonizing PPARγ promoted LPS‐stimulated changes in polarization from the M1 to the M2 phenotype in primary microglia. PPARγ antagonist T0070907 increased the expression of M2 markers, including CD206, IL‐4, IGF‐1, TGF‐β1, TGF‐β2, TGF‐β3, G‐CSF, and GM‐CSF, and reduced the expression of M1 markers, such as CD86, Cox‐2, iNOS, IL‐1β, IL‐6, TNF‐α, IFN‐γ, and CCL2, thereby inhibiting NFκB–IKKβ activation. Moreover, antagonizing PPARγ promoted microglial autophagy, as indicated by the downregulation of P62 and the upregulation of Beclin1, Atg5, and LC3‐II/LC3‐I, thereby enhancing the formation of autophagosomes and their degradation by lysosomes in microglia. Furthermore, we found that an increase in LKB1–STRAD–MO25 complex formation enhances autophagy. The LKB1 inhibitor radicicol or knocking down LKB1 prevented autophagy improvement and the M1‐to‐M2 phenotype shift by T0070907. Simultaneously, we found that knocking down PPARγ in BV2 microglial cells also activated LKB1–AMPK signaling and inhibited NFκB–IKKβ activation, which are similar to the effects of antagonizing PPARγ. Taken together, our findings demonstrate that antagonizing PPARγ promotes the M1‐to‐M2 phenotypic shift in LPS‐induced microglia, which might be due to improved autophagy via the activation of the LKB1–AMPK signaling pathway.

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Section: Resultsmentioning

confidence: 96%

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

et al. 2018

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“…We first examined whether SESN2 regulates the activity of AMPK and MTOR signaling in BMDMs upon stimulation, since SESN2 regulates the activity of AMPK and MTOR in response to genotoxic stress, 24 and AMPK and MTOR are closely involved in the initiation of autophagy in response to nutrient depletion. [42][43][44] The extent of phosphorylation of AMPK, RPS6 (ribosomal protein S6), and ACACA (acetyl-Coenzyme A carboxylase a) were not affected by the deletion of Sesn2 (Fig. S16), indicating that SESN2 is not involved in the activation of the AMPK or MTOR signaling pathways in response to LPS and ATP in macrophages.…”

Section: Sesn2 Induces Autophagic Activity For Mitophagy By Increase mentioning

confidence: 93%

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

et al. 2016

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Proper regulation of mitophagy for mitochondrial homeostasis is important in various inflammatory diseases. However, the precise mechanisms by which mitophagy is activated to regulate inflammatory responses remain largely unknown. The NLRP3 (NLR family, pyrin domain containing 3) inflammasome serves as a platform that triggers the activation of CASP1 (caspase 1) and secretion of proinflammatory cytokines. Here, we demonstrate that SESN2 (sestrin 2), known as stress-inducible protein, suppresses prolonged NLRP3 inflammasome activation by clearance of damaged mitochondria through inducing mitophagy in macrophages. SESN2 plays a dual role in inducing mitophagy in response to inflammasome activation. First, SESN2 induces "mitochondrial priming" by marking mitochondria for recognition by the autophagic machinery. For mitochondrial preparing, SESN2 facilitates the perinuclear-clustering of mitochondria by mediating aggregation of SQSTM1 (sequestosome 1) and its binding to lysine 63 (Lys63)-linked ubiquitins on the mitochondrial surface. Second, SESN2 activates the specific autophagic machinery for degradation of primed mitochondria via an increase of ULK1 (unc-51 like kinase 1) protein levels. Moreover, increased SESN2 expression by extended LPS (lipopolysaccharide) stimulation is mediated by NOS2 (nitric oxide synthase 2, inducible)-mediated NO (nitric oxide) in macrophages. Thus, Sesn2-deficient mice displayed defective mitophagy, which resulted in hyperactivation of inflammasomes and increased mortality in 2 different sepsis models. Our findings define a unique regulatory mechanism of mitophagy activation for immunological homeostasis that protects the host from sepsis.

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“…[24][25][26][27][28][29][30] To address this issue, we examined AMPK-modulated autophagy by determining the LC3-II level, which is a marker of autophagy. The amount of LC3-II is higher in HEK293T cells treated with AICAR, a known AMPK activator (Fig.…”

Section: Ampk Is Required For Autophagy Inductionmentioning

confidence: 99%

AMPK regulates autophagy by phosphorylating BECN1 at threonine 388

et al. 2016

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Macroautophagy/autophagy is a conserved catabolic process that recycles cytoplasmic material during low energy conditions. BECN1/Beclin1 (Beclin 1, autophagy related) is an essential protein for function of the class 3 phosphatidylinositol 3-kinase (PtdIns3K) complexes that play a key role in autophagy nucleation and elongation. Here, we show that AMP-activated protein kinase (AMPK) regulates autophagy by phosphorylating BECN1 at Thr388. Phosphorylation of BECN1 is required for autophagy upon glucose withdrawal. BECN1 T388A , a phosphorylation defective mutant, suppresses autophagy through decreasing the interaction between PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3) and ATG14 (autophagy-related 14). The BECN1 T388A mutant has a higher affinity for BCL2 than its wild-type counterpart; the mutant is more prone to dimer formation. Conversely, a BECN1 phosphorylation mimic mutant, T388D, has stronger binding to PIK3C3 and ATG14, and promotes higher autophagy activity than the wild-type control. These findings uncover a novel mechanism of autophagy regulation.

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AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation

Abstract: View related articles Citing articles: 111 View citing articles ©2 0 1 1 L a n d e s B i o s c i e n c e. D o n o t d i s t r i b u t e .

Cited by 172 publications

References 0 publications

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages

AMPK regulates autophagy by phosphorylating BECN1 at threonine 388

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