Spatial regulation of AMPK signaling revealed by a sensitive kinase activity reporter

Schmitt, Danielle L.; Curtis, Stephanie D.; Lyons, Anne; Zhang, Jinfan; Chen, Mingyuan; He, Catherine Y.; Mehta, Sohum; Shaw, Reuben J.; Zhang, Jin

doi:10.1038/s41467-022-31190-x

Cited by 29 publications

(37 citation statements)

References 81 publications

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“…In mammalian cells, different compartmentalized AMPK pools are activated depending on the severity of the nutrient or energy stress (Zong et al, 2019). While lysosomal AMPK appears to be activated by LKB1 during low glucose stress independent of nucleotide charge, a mitochondrial pool is activated by the alternative upstream kinase CaMKK2 during severe stress conditions associated with increased relative AMP levels (Schmitt et al, 2022). Our analyses indicate that there are no alternative SnRK11 upstream kinases for the GRIK proteins in control conditions in Arabidopsis, but we cannot exclude stress-dependent GRIK relocalization or activity of alternative SnRK1-activating kinases recruiting SnRK1 to other organelles or locations in the cell (Gutierrez-Beltran et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

S-acylation and tonoplast localization of the Geminivirus Rep-Interacting Kinase/SnRK1-Activating Kinase (GRIK/SnAK) proteins differentially regulate salt and energy stress responses in Arabidopsis

Crepin

Rolland

2023

Preprint

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SnRK1 and SnRK3.11/SOS2 are key protein kinases in plant cellular energy and salt stress signaling, respectively. Using cellular assays, we confirm that the GRIK/SnAK (Geminivirus Rep-Interacting Kinase/SnRK1-Activating Kinase) proteins act as their main activating upstream kinases in Arabidopsis, catalyzing T-loop phosphorylation on the SnRK1 alpha1 T175 and SOS2 T168 residues. Remarkably, SnRK1 alpha1 phosphorylation on the neighbouring S176 residue competes with GRIK-mediated T175 phosphorylation to negatively regulate SnRK1 activity. Cellular assays and transgenic plants also revealed that the GRIK proteins, via N-terminal S-acylation, are predominantly localized at the tonoplast, where they interact with SnRK1alpha1 and SOS2. We optimized a leaf mesophyll protoplast-based Acyl PEG Exchange (APE) protocol to further explore GRIK protein S-acylation and tonoplast recruitment and identified the amino acid residues involved. GRIK1 tonoplast localization is likely mediated by initial membrane sampling via N-terminal domain hydrophobicity and local S-acylation, independently of a secretory pathway. Finally, grik1-1 grik2-1 double KO mutants complemented with a non-S-acylatable mutant GRIK1 protein exhibit increased salt sensitivity (reduced SOS2 activity) but hyperactive SnRK1 signaling, demonstrating the differential importance of GRIK subcellular localization for Arabidopsis salt and energy stress responses.

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Section: Discussionmentioning

confidence: 99%

S-acylation and tonoplast localization of the Geminivirus Rep-Interacting Kinase/SnRK1-Activating Kinase (GRIK/SnAK) proteins differentially regulate salt and energy stress responses in Arabidopsis

Crepin

Rolland

2023

Preprint

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“…Recent work investigating the subcellular localization of AMPK suggests that nuclear AMPK controls transcriptional regulators of skeletal muscle plasticity. 36,37 To evaluate whether this phenomenon is evident in the dystrophic context, we measured the presence of myonuclear AMPK in the GAST muscles of Veh-treated WT mice and Veh-and MK-treated mdx animals. The purity of our nuclear samples was confirmed by probing for histone H3 and GAPDH protein content.…”

Section: A Single Dose Of Mk Evokes Ampk Activation In Dystrophic Ske...mentioning

confidence: 99%

Acute, next‐generation AMPK activation initiates a disease‐resistant gene expression program in dystrophic skeletal muscle

Mikhail

Mattina

et al. 2023

The FASEB Journal

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Duchenne muscular dystrophy (DMD) is a life‐limiting neuromuscular disorder characterized by muscle weakness and wasting. Previous proof‐of‐concept studies demonstrate that the dystrophic phenotype can be mitigated with the pharmacological stimulation of AMP‐activated protein kinase (AMPK). However, first‐generation AMPK activators have failed to translate from bench to bedside due to either their lack of potency or toxic, off‐target effects. The identification of safe and efficacious molecules that stimulate AMPK in dystrophic muscle is of particular importance as it may broaden the therapeutic landscape for DMD patients regardless of their specific dystrophin mutation. Here, we demonstrate that a single dose of the next generation, orally‐bioactive AMPK agonist MK‐8722 (MK) to mdx mice evoked skeletal muscle AMPK and extensive downstream stimulation within 12 h post‐treatment. Specifically, MK elicited a gene expression profile indicative of a more disease‐resistant slow, oxidative phenotype including increased peroxisome proliferator‐activated receptor ɣ coactivator‐1⍺ activity and utrophin levels. In addition, we observed augmented autophagy signaling downstream of AMPK, as well as elevations in critical autophagic genes such as Map1lc3 and Sqstm1 subsequent to the myonuclear accumulation of the master regulator of the autophagy gene program, transcription factor EB. Lastly, we show that pharmacological AMPK stimulation normalizes the expression of myogenic regulatory factors and amends activated muscle stem cell content in mdx muscle. Our results indicate that AMPK activation via MK enhances disease‐mitigating mechanisms in dystrophic muscle and prefaces further investigation on the chronic effects of novel small molecule AMPK agonists.

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“…AMPK regulates cellular energy synthesis and catabolism. It is also an essential cell growth, reproduction, and autophagy regulator (Schmitt et al, 2022). AMPK is a crucial receptor for cellular energy.…”

Section: Introductionmentioning

confidence: 99%

Combined β-Sitosterol and Trimetazidine mitigate potassium dichromate-induced cardiotoxicity in rats through the interplay between NF-κB/AMPK/mTOR/TLR4 and HO-1/NADPH signaling pathways

El-Shoura

Salem

Ahmed

et al. 2023

Preprint

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Hexavalent chromium salt, like potassium dichromate (PD), is chromium's most precarious valence state, present in industrial wastes. Recently, there has been increasing interest in β-sitosterol (BSS), a bioactive phytosterol, as a dietary supplement. BSS is recommended in treating cardiovascular disorders due to its antioxidant effect. Trimetazidine (TMZ) was used traditiovally for cardioprotection. Through the administration of BSS and TMZ, the cardiotoxic effects of PD were to be countered in this study, in addition to examining the precise mechanism of PD-induced cardiotoxicity. Thirty male albino rats were divided into five groups; the control group: administered normal saline daily (3 mL/kg); the PD group: administered normal saline daily (3 mL/kg); BSS group: administered BSS daily (20 mg/kg); TMZ group: administered TMZ daily (15 mg/kg). BSS+TMZ group: administered both BSS (20 mg/kg) and TMZ (15 mg/kg) daily. All experimental groups, except the control, received on the 19th day a single dose of PD (30 mg/kg/day, SC). Normal saline, BSS, and TMZ were received daily for 21 consecutive days orally. The exposure to PD promoted different oxidative stress, proinflammatory, and cardiotoxicity biomarkers. BSS or TMZ succeeded solely in reducing this deleterious effect; however, their combination notably returns measured biomarkers close to normal values. The histopathological investigations have supported the biochemical findings. The combination of BSS and TMZ protects against PD cardiotoxicity in rats by reducing oxidative stress and apoptotic and inflammatory biomarkers. It may be promising for alleviating and treating PD-induced cardiotoxicity in people at an early stage.

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Spatial regulation of AMPK signaling revealed by a sensitive kinase activity reporter

Cited by 29 publications

References 81 publications

S-acylation and tonoplast localization of the Geminivirus Rep-Interacting Kinase/SnRK1-Activating Kinase (GRIK/SnAK) proteins differentially regulate salt and energy stress responses in Arabidopsis

S-acylation and tonoplast localization of the Geminivirus Rep-Interacting Kinase/SnRK1-Activating Kinase (GRIK/SnAK) proteins differentially regulate salt and energy stress responses in Arabidopsis

Acute, next‐generation AMPK activation initiates a disease‐resistant gene expression program in dystrophic skeletal muscle

Combined β-Sitosterol and Trimetazidine mitigate potassium dichromate-induced cardiotoxicity in rats through the interplay between NF-κB/AMPK/mTOR/TLR4 and HO-1/NADPH signaling pathways

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