mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress

Ling, Naomi X.Y.; Kaczmarek, Adrian; Hoque, Ashfaqul; Davie, Elizabeth A. Colby; Ngoei, Kevin R.W.; Morrison, Kaitlin R.; Smiles, William J.; Forte, Gabriella; Wang, Tingting; Lie, Shervi; Dite, Toby A.; Langendorf, Christopher G.; Scott, John W.; Oakhill, Jonathan S.; Petersen, Janni

doi:10.1038/s42255-019-0157-1

Cited by 121 publications

(108 citation statements)

References 40 publications

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“…4. The crosstalk between these signaling pathways can occur through the direct reciprocal antagonism, such as between mTORC1 and AMPK 190,207,242 or Akt and LKB1, 187 or via indirect inhibition of downstream signaling effectors. For example, the ULK1 complex, which promotes autophagy, is inhibited and activated by mTORC1 and AMPK signaling, respectively.…”

Section: Immunometabolic Signaling Networkmentioning

confidence: 99%

Signaling networks in immunometabolism

Saravia¹,

Raynor²,

Chapman³

et al. 2020

Cell Res

163

136

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Adaptive immunity is essential for pathogen and tumor eradication, but may also trigger uncontrolled or pathological inflammation. T cell receptor, co-stimulatory and cytokine signals coordinately dictate specific signaling networks that trigger the activation and functional programming of T cells. In addition, cellular metabolism promotes T cell responses and is dynamically regulated through the interplay of serine/threonine kinases, immunological cues and nutrient signaling networks. In this review, we summarize the upstream regulators and signaling effectors of key serine/threonine kinase-mediated signaling networks, including PI3K-AGC kinases, mTOR and LKB1-AMPK pathways that regulate metabolism, especially in T cells. We also provide our perspectives about the pending questions and clinical applicability of immunometabolic signaling. Understanding the regulators and effectors of immunometabolic signaling networks may uncover therapeutic targets to modulate metabolic programming and T cell responses in human disease.

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Section: Immunometabolic Signaling Networkmentioning

confidence: 99%

Signaling networks in immunometabolism

Saravia¹,

Raynor²,

Chapman³

et al. 2020

Cell Res

163

136

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“…This lipotoxicity was associated with a sustained mTOR activation, but the association with AMPK was not explored. Excessive fat also induces constitutive activation of mTORC1 that directly inhibits AMPK activity, suggesting a link between mTOR and AMPK [156,157]. However, AMPK-mediated activation of autophagy protects against renal injury, particularly in AKI [158].…”

Section: Ampk and The Regulation Of Renal Autophagy And Mitophagymentioning

confidence: 99%

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

Juszczak

Caron

Mathew

et al. 2020

IJMS

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Chronic kidney disease (CKD) is prevalent in 9.1% of the global population and is a significant public health problem associated with increased morbidity and mortality. CKD is associated with highly prevalent physiological and metabolic disturbances such as hypertension, obesity, insulin resistance, cardiovascular disease, and aging, which are also risk factors for CKD pathogenesis and progression. Podocytes and proximal tubular cells of the kidney strongly express AMP-activated protein kinase (AMPK). AMPK plays essential roles in glucose and lipid metabolism, cell survival, growth, and inflammation. Thus, metabolic disease-induced renal diseases like obesity-related and diabetic chronic kidney disease demonstrate dysregulated AMPK in the kidney. Activating AMPK ameliorates the pathological and phenotypical features of both diseases. As a metabolic sensor, AMPK regulates active tubular transport and helps renal cells to survive low energy states. AMPK also exerts a key role in mitochondrial homeostasis and is known to regulate autophagy in mammalian cells. While the nutrient-sensing role of AMPK is critical in determining the fate of renal cells, the role of AMPK in kidney autophagy and mitochondrial quality control leading to pathology in metabolic disease-related CKD is not very clear and needs further investigation. This review highlights the crucial role of AMPK in renal cell dysfunction associated with metabolic diseases and aims to expand therapeutic strategies by understanding the molecular and cellular processes underlying CKD.

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“…In support of this notion, Aster‐C deficiency also led to accumulation of LC3‐II during starvation (Fig EV2C). A recent study demonstrated that mTORC1 directly inhibits AMPK signaling (Ling et al , ). Consistent with the hyper‐activation of mTORC1 in Aster‐C KO cells, the phosphorylation level of ULK1 at S555, a key phosphorylation site by AMPK (Egan et al , ,b), is significantly lower in Aster‐C KO cells during nutrient starvation (Fig EV2C).…”

Section: Resultsmentioning

confidence: 99%

Aster‐C coordinates with COP I vesicles to regulate lysosomal trafficking and activation of mTORC1

Zhang¹,

Andersen²,

Sun

et al. 2020

EMBO Reports

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Nutrient sensing by the mTOR complex 1 (mTORC1) requires its translocation to the lysosomal membrane. Upon amino acids removal, mTORC1 becomes cytosolic and inactive, yet its precise subcellular localization and the mechanism of inhibition remain elusive. Here, we identified Aster‐C as a negative regulator of mTORC1 signaling. Aster‐C earmarked a special rough ER subdomain where it sequestered mTOR together with the GATOR2 complex to prevent mTORC1 activation during nutrient starvation. Amino acids stimulated rapid disassociation of mTORC1 from Aster‐C concurrently with assembly of COP I vesicles which escorted mTORC1 to the lysosomal membrane. Consequently, ablation of Aster‐C led to spontaneous activation of mTORC1 and dissociation of TSC2 from lysosomes, whereas inhibition of COP I vesicle biogenesis or actin dynamics prevented mTORC1 activation. Together, these findings identified Aster‐C as a missing link between lysosomal trafficking and mTORC1 activation by revealing an unexpected role of COP I vesicles in mTORC1 signaling.

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mTORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress

Cited by 121 publications

References 40 publications

Signaling networks in immunometabolism

Signaling networks in immunometabolism

Critical Role for AMPK in Metabolic Disease-Induced Chronic Kidney Disease

Aster‐C coordinates with COP I vesicles to regulate lysosomal trafficking and activation of mTORC1

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