The AMPK-PP2A axis in insect fat body is activated by 20-hydroxyecdysone to antagonize insulin/IGF signaling and restrict growth rate

Yuan, Dong‐Wei; Zhou, Shun; Liu, Suning; Li, Kang; Zhao, Haigang; Long, Shihui; Liu, Hanhan; Xie, Yongfang; Yan, Su; Yu, Fengwei; Li, Sheng

doi:10.1073/pnas.2000963117

Cited by 49 publications

(64 citation statements)

References 72 publications

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“…Serum deprivation deinhibits glycogen synthase kinase-3 (GSK3), which promotes the phosphorylation of BmTip60 at Ser86, and subsequent activation of autophagy through the acetylation of ULK1 [26], whereas autophagy is as effectively induced by serum starvation in AMPKα1/2-DKO (double knockout) mouse embryonic fibroblast (MEF) cells as in control cells, indicating the independence of AMPK in autophagy induction in this case [26,27]. In B. mori, comparisons between the variations of BmTip60 proteins, autophagy occurrence, and nutrient signals including p-InR, p-4EBP, and p-AMPK from 5L2D to PP2 in fat body suggested that AMPK is the most possible protein kinase to phosphorylate BmTip60 at the late larval and prepupal stages [5,33,40]. As expected, metformin and compound C treatments, which activate and inhibit AMPK activity, result in the induction and abolishment of BmTip60 protein migration.…”

Section: Phosphorylation Of Bmtip60 Is Regulated By Ampk Activity Andmentioning

confidence: 98%

“…Thus, we questioned whether AMPK activity was involved in regulating the migration of BmTip60 proteins. Metformin, the AMPK-specific activator, was injected into 5L3D larvae when AMPK activity is low [33,40]. After metformin treatment for 24 h, fat body was collected for Western blots and immunofluorescent staining.…”

Section: Ampk Activity Mediates the Migration Of Bmtip60 Proteinmentioning

confidence: 99%

“…Starvation and 20E are the two major stimuli of autophagy in insects [5,7,35,43]. In B. mori and D. melanogaster, 20E-EcR/USP signaling predominantly upregulates autophagy through the induction of Atg gene expression in addition to antagonizing insulin/insulin-like growth factor (IGF) signaling (IIS) [5,33]. The 20E primary-response genes such as E75 and E93 are pivotal for 20E-induced autophagy during larval-pupal metamorphosis [6,44].…”

Section: E Functions Differently With Starvation In Regulating Bmtip60mentioning

confidence: 99%

“…20E and starvation treatments both induce the gene expressions of B. mori V-ATPases subunits and their assembly through the activation of transcription factor TFEB and inhibition of MTOR activity, resulting in lysosome acidification and autophagic flux [36]. In addition, 20E induces starvation-like conditions by reducing food consumption [5,33,45]. In general, 20E interacts closely with starvation signals, and they function similarly to each other in regulating autophagosome formation as well as autophagic flux in most cases.…”

Section: E Functions Differently With Starvation In Regulating Bmtip60mentioning

confidence: 99%

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Tip60 Phosphorylation at Ser 99 Is Essential for Autophagy Induction in Bombyx mori

Zhao

et al. 2020

IJMS

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Tip60, a key histone acetyltransferase of the MYST family and member of the nuclear multimeric protein complex (NuA4), regulates the activity and stability of proteins involved in the cell cycle, DNA damage responses, autophagy, etc. However, the function and regulatory mechanism of Tip60 homolog in Bombyx mori are not elucidated. In the present study, Bombyx Tip60 (BmTip60) was functionally identified. Developmental profiles showed that the protein levels and nuclear localization of BmTip60 peaked in fat body during the larval–pupal metamorphosis when autophagy was intensive; simultaneously, the BmTip60 protein migrated to form an upper band as detected by Western blot. Interestingly, the upper band of BmTip60 was reduced by λ-phosphatase treatment, indicating that it was a phosphorylated form of BmTip60. Results showed that BmTip60 was promoted by starvation but not 20-hydroxyecdysone treatment. Transcription factor AMP-activated protein kinase (AMPK) affected by starvation was pivotal for BmTip60 protein migration. In addition, one mammalian phosphorylation site was identified in BmTip60 at Ser99, the constitutive-activation mutation of Ser99 to Asp99 but not its inactive mutation to Ala99 significantly upregulated autophagy, showing the critical role of phosphorylation at Ser99 for BmTip60-mediated autophagy. In conclusion, the starvation-AMPK axis promotes BmTip60 in B. mori, which was requisite for autophagy induction. These results reveal a regulatory mechanism of histone acetyltransferase Tip60 homologs by phosphorylation in insects, and sheds light on further related studies of acetylation regulation.

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Section: Phosphorylation Of Bmtip60 Is Regulated By Ampk Activity Andmentioning

confidence: 98%

Section: Ampk Activity Mediates the Migration Of Bmtip60 Proteinmentioning

confidence: 99%

Section: E Functions Differently With Starvation In Regulating Bmtip60mentioning

confidence: 99%

Section: E Functions Differently With Starvation In Regulating Bmtip60mentioning

confidence: 99%

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Tip60 Phosphorylation at Ser 99 Is Essential for Autophagy Induction in Bombyx mori

Zhao

et al. 2020

IJMS

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“…The expression of the ULK1 and EIF4EBP1 genes was downregulated in the subcutaneous fat of the yaks under ES ( q < 0.01), and it was inferred that cell growth and protein synthesis in the subcutaneous fat of the yaks under long-term ES were inhibited and energy expenditure was decreased. Moreover, the PI3K-Akt signaling, which is also mainly related to energy metabolism, was also activated [ 55 , 56 , 57 ]. The expression of the PIK3R1 gene was upregulated in the subcutaneous fat of the yaks under ES ( q < 0.05), and the expression of the AKT1 and AKT2 genes was downregulated ( q < 0.01).…”

Section: Discussionmentioning

confidence: 99%

The Study of the Response of Fat Metabolism to Long-Term Energy Stress Based on Serum, Fatty Acid and Transcriptome Profiles in Yaks

Xiong

Pei

et al. 2020

Animals

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Long-term energy stress (ES) during the cold season is a serious problem for the breeding of yaks. In this paper, the response of fat metabolism in yaks to long-term ES during the cold season was studied. Gas chromatography (GC) analysis showed that the percentage of saturated fatty acids (SFAs) in the subcutaneous fat of the yaks in the ES group was 42.7%, which was less than the 56.6% in the CO group (p < 0.01) and the percentage of polyunsaturated unsaturated fatty acids (PUFAs) in the subcutaneous fat of the yaks in the ES group was 38.3%, which was more than the 26.0% in the CO group (p < 0.01). The serum analysis showed that fatty acid oxidation in yaks was increased under long-term ES. In the subcutaneous fat of yaks under long-term ES, the gene expression levels of glycerol-3-phosphate acyltransferase 4 (GPAT4), hormone-sensitive lipase (HSL), patatin-like phospholipase domain-containing protein 2 (PNPLA2), acyl-CoA dehydrogenase (ACAD), acyl-coenzyme A thioesterase 8 (ACOT8), facilitated glucose transporter (GLUT4), 3-oxoacyl-[acyl-carrier-protein] synthase (OXSM), oestradiol 17-beta-dehydrogenase 8 (HSD17B8) and malonate-Co-A ligase ACSF3 (ACSF3) were downregulated (q < 0.05), whereas the gene expression levels of aquaporin-7 (AQP7), long-chain-fatty-acid-CoA ligase (ACSL), elongation of very long chain fatty acids protein (ELOVL) and fatty acid desaturase 1 (FADS1) were upregulated (q < 0.05), indicating the inhibition of fat catabolism, fat anabolism, fatty acid oxidation, glucose (GLU) intake and SFA synthesis and the promotion of glycerinum (GLY) transportation and PUFA synthesis. Additional findings showed that the gene expression levels of leptin (LEP), adenosine 5′-monophosphate-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3K) were upregulated (q < 0.05), whereas the gene expression levels of malonyl-CoA decarboxylase (MCD), sterol regulatory element-binding protein 1 (SREBF1), mammalian target of rapamycin (mTOR) and serine/threonine-protein kinase (AKT) were downregulated (q < 0.05), indicating that fat metabolism in the subcutaneous fat of yaks under ES was mainly regulated by AMPK signaling and mTOR and PI3K-AKT signaling were also involved. Energy consumption was inhibited in the subcutaneous fat itself. This study can provide a theoretical basis for the healthy breeding and genetic breeding of yaks.

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Genetic analysis and transcriptome analysis of the mini mutant of the silkworm, Bombyx mori

Gao

Mei

Liu

et al. 2021

Arch Insect Biochem Physiol

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The expression levels of some intrinsic genes, protease activity, and regulation of signaling pathways were distinct during different growth and development stages in the silkworm, Bombyx mori. The silkworm mutant mini was discovered from the normal silkworm strain S8V, and the body‐size of the mini mutant was smaller than the wild‐type from the second‐instar and the difference became more significant in the following stages. In this study, genetic analysis of mini mutant showed that mini mutant was controlled by a single recessive gene, manifested as homozygous lethal. Then, the transcriptome analysis of the mini mutant indicated that 2944 differentially expressed genes (DEGs) were identified from the silkworm in the 48 h of the second‐instar, of which 1638 genes in the mini mutants were upregulated and 1306 genes were downregulated. These DEGs were mainly distributed in the biological process, cellular component, and molecular function. The functional annotation based on the KEGG database showed that these genes were mainly clustered in metabolic pathways, fatty acid metabolism pathways, ribosome biogenesis in eukaryotes, and so on. Further analysis indicated that some genes involved in the growth and metabolism including enzyme genes, juvenile hormone, and ecdysone exhibited different transcriptional levels. These results provided new experimental evidence regarding the mechanism of the underlying formation of mini mutants.

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The AMPK-PP2A axis in insect fat body is activated by 20-hydroxyecdysone to antagonize insulin/IGF signaling and restrict growth rate

Cited by 49 publications

References 72 publications

Tip60 Phosphorylation at Ser 99 Is Essential for Autophagy Induction in Bombyx mori

Tip60 Phosphorylation at Ser 99 Is Essential for Autophagy Induction in Bombyx mori

The Study of the Response of Fat Metabolism to Long-Term Energy Stress Based on Serum, Fatty Acid and Transcriptome Profiles in Yaks

Genetic analysis and transcriptome analysis of the mini mutant of the silkworm, Bombyx mori

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