scholarly journals Nutrient-dependent mTORC1 signaling in coral-algal symbiosis

2019 ◽  
Author(s):  
Philipp A. Voss ◽  
Sebastian G. Gornik ◽  
Marie R. Jacobovitz ◽  
Sebastian Rupp ◽  
Melanie S. Dörr ◽  
...  
Keyword(s):  
Nutrient Sensing ◽  
Host Cells ◽  
Coral Host ◽  
Metabolic Switch ◽  
Animal Development ◽  
Mtorc1 Signaling ◽  
Algal Symbiosis ◽  
Mtorc1 Pathway ◽  
Symbiosis Model ◽  
Endodermal Cells

SummaryTo coordinate development and growth with nutrient availability, animals must sense nutrients and acquire food from the environment once energy is depleted. A notable exception are reef-building corals that form a stable symbiosis with intracellular photosynthetic dinoflagellates (family Symbiodiniaceae (LaJeunesse et al., 2018)). Symbionts reside in ‘symbiosomes’ and transfer key nutrients to support nutrition and growth of their coral host in nutrient-poor environments (Muscatine, 1990; Yellowlees et al., 2008). To date, it is unclear how symbiont-provided nutrients are sensed to adapt host physiology to this endosymbiotic life-style. Here we use the symbiosis model Exaiptasia pallida (hereafter Aiptasia) to address this. Aiptasia larvae, similar to their coral relatives, are naturally non-symbiotic and phagocytose symbionts anew each generation into their endodermal cells (Bucher et al., 2016; Grawunder et al., 2015; Hambleton et al., 2014). Using cell-specific transcriptomics, we find that symbiosis establishment results in downregulation of various catabolic pathways, including autophagy in host cells. This metabolic switch is likely triggered by the highly-conserved mTORC1 (mechanistic target of rapamycin complex 1) signaling cascade, shown to integrate lysosomal nutrient abundance with animal development (Perera and Zoncu, 2016). Specifically, symbiosomes are LAMP1-positive and recruit mTORC1 kinase. In symbiotic anemones, mTORC1 signaling is elevated when compared to non-symbiotic animals, resembling a feeding response. Moreover, symbiosis establishment enhances lipid content and cell proliferation in Aiptasia larvae. Challenging the prevailing belief that symbiosomes are early arrested phagosomes (Mohamed et al., 2016), we propose a model in which symbiosomes functionally resemble lysosomes as core nutrient sensing and signaling hubs that have co-opted the evolutionary ancient mTORC1 pathway to promote growth in endosymbiotic cnidarians.

scholarly journals Modulation of mTORC1 Signaling Pathway by HIV-1

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1090 ◽  
Author(s):  
Burkitkan Akbay ◽  
Anna Shmakova ◽  
Yegor Vassetzky ◽  
Svetlana Dokudovskaya
Keyword(s):  
Cellular Response ◽  
Cellular Proliferation ◽  
Mammalian Target Of Rapamycin ◽  
Host Cells ◽  
Promising Strategy ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Recent Trends ◽  
Hiv 1

Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular proliferation and survival which controls cellular response to different stresses, including viral infection. HIV-1 interferes with the mTORC1 pathway at every stage of infection. At the same time, the host cells rely on the mTORC1 pathway and autophagy to fight against virus replication and transmission. In this review, we will provide the most up-to-date picture of the role of the mTORC1 pathway in the HIV-1 life cycle, latency and HIV-related diseases. We will also provide an overview of recent trends in the targeting of the mTORC1 pathway as a promising strategy for HIV-1 eradication.

scholarly journals A lipid-mTORC1 nutrient-sensing pathway regulates animal development by peroxisome-derived hormones

2021 ◽  
Author(s):  
Na Li ◽  
Beilei Hua ◽  
qing chen ◽  
Meiyu Ruan ◽  
Mengnan ZHU ◽  
...  
Keyword(s):  
Large Scale ◽  
Amino Acid Level ◽  
Nutrient Sensing ◽  
Whole Body ◽  
Apical Region ◽  
Beta Oxidation ◽  
Dependent Development ◽  
Animal Development ◽  
Signaling Mechanisms ◽  
Mtorc1 Pathway

Animals have developed many signaling mechanisms that alter cellular and developmental programs in response to changes in nutrients and their derived metabolites, many of which remain to be understood. We recently uncovered that glucosylceramides, a core sphingolipid, act as a critical nutrient signal for overall amino-acid level to promote development by activating the intestinal mTORC1 pathway. However, how the intestinal GlcCer-mTORC1 activity regulates development throughout the whole body is unknown. Through a large-scale genetic screen, we found that the peroxisomes are critical for antagonizing the GlcCer-mTORC1-mediated nutrient signal. Mechanistically, deficiency of glucosylceramide, inactivation of the downstream mTORC1 activity, or prolonged starvation relocated peroxisomes closer to the intestinal apical region to release peroxisomal-beta-oxidation derived hormones that targeting chemosensory neurons to arrest the animal development. Our data illustrated a new gut-brain axis for orchestrating nutrient-sensing dependent development in Caenorhabditis elegans, which may also explain why glucosylceramide and peroxisome become essential in metazoans.

scholarly journals Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+-mediated mechanism in the human pancreatic carcinoma cell line PANC-1

2015 ◽  
Vol 309 (10) ◽  
pp. C639-C649 ◽  
Author(s):  
Hui-Hua Chang ◽  
Steven H. Young ◽  
James Sinnett-Smith ◽  
Caroline Ei Ne Chou ◽  
Aune Moro ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Pancreatic Cancer ◽  
Prostaglandin E2 ◽  
Human Pancreatic Cancer ◽  
Pancreatic Carcinoma Cell Line ◽  
Pancreatic Cancer Cells ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Pka Pathway ◽  
Mtorc1 Activation

Obesity, a known risk factor for pancreatic cancer, is associated with inflammation and insulin resistance. Proinflammatory prostaglandin E2 (PGE2) and elevated insulin-like growth factor type 1 (IGF-1), related to insulin resistance, are shown to play critical roles in pancreatic cancer progression. We aimed to explore a potential cross talk between PGE2 signaling and the IGF-1/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway in pancreatic cancer, which may be a key to unraveling the obesity-cancer link. In PANC-1 human pancreatic cancer cells, we showed that PGE2 stimulated mTORC1 activity independently of Akt, as evaluated by downstream signaling events. Subsequently, using pharmacological and genetic approaches, we demonstrated that PGE2-induced mTORC1 activation is mediated by the EP4/cAMP/PKA pathway, as well as an EP1/Ca2+-dependent pathway. The cooperative roles of the two pathways were supported by the maximal inhibition achieved with the combined pharmacological blockade, and the coexistence of highly expressed EP1 (mediating the Ca2+ response) and EP2 or EP4 (mediating the cAMP/PKA pathway) in PANC-1 cells and in the prostate cancer line PC-3, which also robustly exhibited PGE2-induced mTORC1 activation, as identified from a screen in various cancer cell lines. Importantly, we showed a reinforcing interaction between PGE2 and IGF-1 on mTORC1 signaling, with an increase in IL-23 production as a cellular outcome. Our data reveal a previously unrecognized mechanism of PGE2-stimulated mTORC1 activation mediated by EP4/cAMP/PKA and EP1/Ca2+ signaling, which may be of great importance in elucidating the promoting effects of obesity in pancreatic cancer. Ultimately, a precise understanding of these molecular links may provide novel targets for efficacious interventions devoid of adverse effects.

Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing

2018 ◽  
Vol 11 (559) ◽  
pp. eaat6903 ◽  
Author(s):  
Julia Sanchez-Garrido ◽  
Vanessa Sancho-Shimizu ◽  
Avinash R. Shenoy
Keyword(s):  
Nutrient Sensing ◽  
Caspase 8 ◽  
Rimmed Vacuoles ◽  
Sequestosome 1 ◽  
Inflammatory Conditions ◽  
Mtorc1 Signaling ◽  
Differential Control ◽  
Antimicrobial Immunity ◽  
Lateral Sclerosis

The multidomain scaffold protein p62 (also called sequestosome-1) is involved in autophagy, antimicrobial immunity, and oncogenesis. Mutations in SQSTM1, which encodes p62, are linked to hereditary inflammatory conditions such as Paget’s disease of the bone, frontotemporal dementia (FTD), amyotrophic lateral sclerosis, and distal myopathy with rimmed vacuoles. Here, we report that p62 was proteolytically trimmed by the protease caspase-8 into a stable protein, which we called p62TRM. We found that p62TRM, but not full-length p62, was involved in nutrient sensing and homeostasis through the mechanistic target of rapamycin complex 1 (mTORC1). The kinase RIPK1 and caspase-8 controlled p62TRM production and thus promoted mTORC1 signaling. An FTD-linked p62 D329G polymorphism and a rare D329H variant could not be proteolyzed by caspase-8, and these noncleavable variants failed to activate mTORC1, thereby revealing the detrimental effect of these mutations. These findings on the role of p62TRM provide new insights into SQSTM1-linked diseases and mTORC1 signaling.

scholarly journals OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance

2020 ◽  
Vol 117 (28) ◽  
pp. 16616-16625
Author(s):  
Yunfan Yang ◽  
Xiruo Li ◽  
Harding H. Luan ◽  
Bichen Zhang ◽  
Kaisi Zhang ◽  
...  
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Nutrient Sensing ◽  
Metabolic Disturbance ◽  
Whole Body ◽  
Metabolic Dysfunction ◽  
Peripheral Tissues ◽  
Mtorc1 Signaling ◽  
Whole Body Metabolism ◽  
Glcnac Transferase

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensingO-linked β-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase inO-GlcNAc signaling in macrophages.O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. SuppressingO-GlcNAc signaling byO-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1)O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophageO-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.

scholarly journals IL-2– and IL-15–induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2181-2189 ◽  
Author(s):  
Michal Marzec ◽  
Xiaobin Liu ◽  
Monika Kasprzycka ◽  
Agnieszka Witkiewicz ◽  
Puthiyaveettil N. Raghunath ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Cell Transformation ◽  
Single Agent ◽  
Large Cell ◽  
Dependent Manner ◽  
T Cell Lymphomas ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Mtorc1 Activation

We examined functional status, activation mechanisms, and biologic role of the mTORC1 signaling pathway in malignant CD4+ T cells derived from the cutaneous T-cell lymphoma (CTCL). Whereas the spontaneously growing CTCL-derived cell lines displayed persistent activation of the TORC1 as well as the PI3K/Akt and MEK/ERK pathways, the IL-2–dependent cell lines activated the pathways in response to IL-2 and IL-15 but not IL-21. Activation of mTORC1 and MEK/ERK was nutrient dependent. The mTORC1, PI3K/Akt, and MEK/ERK pathways could also be activated by IL-2 in the primary leukemic, mitogen-preactivated CTCL cells. mTORC1 activation was also detected in the CTCL tissues in the lymphoma stage–dependent manner with the highest percentage of positive cells present in the cases with a large cell transformation. Rapamycin inhibited mTORC1 signaling and suppressed CTCL cell proliferation but showed little effect on their apoptotic rate when used as a single agent. Activation of the mTORC1, PI3K/Akt, and MEK/ERK pathways was strictly dependent on the Jak3 and Jak1 kinases. Finally, mTORC1 activation was transduced preferentially through the PI3K/Akt pathway. These findings document the selective γc-signaling cytokine-mediated activation of the mTORC1 pathway in the CTCL cells and suggest that the pathway represents a therapeutic target in CTCL and, possibly, other T-cell lymphomas.

scholarly journals Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction

2021 ◽  
Vol 118 (4) ◽  
pp. e2022120118
Author(s):  
Kendall J. Condon ◽  
Jose M. Orozco ◽  
Charles H. Adelmann ◽  
Jessica B. Spinelli ◽  
Pim W. van der Helm ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mammalian Cells ◽  
Growth Control ◽  
Screening Strategy ◽  
Genome Wide ◽  
Mtorc1 Signaling ◽  
Full Complement ◽  
Mtorc1 Pathway ◽  
Synthase Inhibitor ◽  
Almost All

In mammalian cells, nutrients and growth factors signal through an array of upstream proteins to regulate the mTORC1 growth control pathway. Because the full complement of these proteins has not been systematically identified, we developed a FACS-based CRISPR-Cas9 genetic screening strategy to pinpoint genes that regulate mTORC1 activity. Along with almost all known positive components of the mTORC1 pathway, we identified many genes that impact mTORC1 activity, including DCAF7, CSNK2B, SRSF2, IRS4, CCDC43, and HSD17B10. Using the genome-wide screening data, we generated a focused sublibrary containing single guide RNAs (sgRNAs) targeting hundreds of genes and carried out epistasis screens in cells lacking nutrient- and stress-responsive mTORC1 modulators, including GATOR1, AMPK, GCN2, and ATF4. From these data, we pinpointed mitochondrial function as a particularly important input into mTORC1 signaling. While it is well appreciated that mitochondria signal to mTORC1, the mechanisms are not completely clear. We find that the kinases AMPK and HRI signal, with varying kinetics, mitochondrial distress to mTORC1, and that HRI acts through the ATF4-dependent up-regulation of both Sestrin2 and Redd1. Loss of both AMPK and HRI is sufficient to render mTORC1 signaling largely resistant to mitochondrial dysfunction induced by the ATP synthase inhibitor oligomycin as well as the electron transport chain inhibitors piericidin and antimycin. Taken together, our data reveal a catalog of genes that impact the mTORC1 pathway and clarify the multifaceted ways in which mTORC1 senses mitochondrial dysfunction.

scholarly journals circRNA LDLRAD3 Enhances the Malignant Behaviors of NSCLC Cells via the miR-20a-5p-SLC7A5 Axis Activating the mTORC1 Signaling Pathway

2022 ◽  
Vol 2022 ◽  
pp. 1-10
Author(s):  
Yu Li ◽  
Guangle Qin ◽  
Jinyun Du ◽  
Peng Yue ◽  
Yanling Zhang ◽  
...  
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Potential Therapeutic Target ◽  
Expression Levels ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Related Proteins

Circular RNA LDLRAD3 behaved as an oncogene in several malignancies, but its effects in NSCLC and the involvement of downstream molecules and activation of signaling pathways had not been fully reported. We planned to explore how LDLRAD3 facilitated the malignancy of NSCLC. QRT-PCR was performed to evaluate the expression levels of LDLRAD3, miR-20a-5p, and SLC7A5 in NSCLC tissues and cells. si-LDLRAD3 was transfected to A549 and H1299 cells to knock down intrinsic LDLRAD3 to determine its oncogenic roles. CCK-8 assay and transwell assay were executed to assess cell proliferative, migrative, and invasive abilities. Dual-luciferase reporter (DLR) assay was manipulated to verify the ENCORI-predicted relationships between LDLRAD3 and miR-20a-5p and between miR-20a-5p and SLC7A5. Western blot, immunofluorescent assay, and immunohistochemistry were applied to explore the expression levels of SLC7A5, and the levels of mTORC1 pathway-related proteins were evaluated using western blot. Rescue experiments were conducted by transfecting si-LDLRAD3, miR-20a-5p inhibitor, and si-SLC7A5 to explore the influence of the LDLRAD3-miR-20a-5p-SLC7A5 axis on the malignant behaviors of NSCLC cells. The expression levels of LDLRAD3 and SLC7A5 were boosted, whereas miR-20a-5p was impeded in NSCLC tissues and cell lines. Knockdown of LDLRAD3 weakened the proliferation, migration, and invasion of A549 and H1299 cells. LDLRAD3 was verified to sponge miR-20a-5p and miR-20a-5p targeted SLC7A5. LDLRAD3 activated the mTORC1 singling pathway via the miR-20a-5p-SLC7A5 axis to strengthen the malignant properties of A549 and H1299 cells. We concluded that LDLRAD3 exerted oncogenic effects via the miR-20a-5p-SLC7A5 axis to activate the mTORC1 signaling pathway in NSCLC. Our findings enlightened that LDLRAD3 could become a potential therapeutic target in the treatment and management of NSCLC.

scholarly journals Heat stress destabilizes symbiotic nutrient cycling in corals

2021 ◽  
Vol 118 (5) ◽  
pp. e2022653118 ◽  
Author(s):  
Nils Rädecker ◽  
Claudia Pogoreutz ◽  
Hagen M. Gegner ◽  
Anny Cárdenas ◽  
Florian Roth ◽  
...  
Keyword(s):  
Heat Stress ◽  
Nutrient Cycling ◽  
Energy Demand ◽  
Metabolic Energy ◽  
Environmental Drivers ◽  
Coral Host ◽  
Stylophora Pistillata ◽  
Coral Holobiont ◽  
Algal Symbiosis ◽  
Energy Limitation

Recurrent mass bleaching events are pushing coral reefs worldwide to the brink of ecological collapse. While the symptoms and consequences of this breakdown of the coral–algal symbiosis have been extensively characterized, our understanding of the underlying causes remains incomplete. Here, we investigated the nutrient fluxes and the physiological as well as molecular responses of the widespread coral Stylophora pistillata to heat stress prior to the onset of bleaching to identify processes involved in the breakdown of the coral–algal symbiosis. We show that altered nutrient cycling during heat stress is a primary driver of the functional breakdown of the symbiosis. Heat stress increased the metabolic energy demand of the coral host, which was compensated by the catabolic degradation of amino acids. The resulting shift from net uptake to release of ammonium by the coral holobiont subsequently promoted the growth of algal symbionts and retention of photosynthates. Together, these processes form a feedback loop that will gradually lead to the decoupling of carbon translocation from the symbiont to the host. Energy limitation and altered symbiotic nutrient cycling are thus key factors in the early heat stress response, directly contributing to the breakdown of the coral–algal symbiosis. Interpreting the stability of the coral holobiont in light of its metabolic interactions provides a missing link in our understanding of the environmental drivers of bleaching and may ultimately help uncover fundamental processes underpinning the functioning of endosymbioses in general.

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