Galectins Control mTOR in Response to Endomembrane Damage

Jia, Jingyue; Abudu, Yakubu Princely; Claude-Taupin, Aurore; Gu, Yuexi; Kumar, Suresh; Choi, Su-Mi; Peters, Ryan; Mudd, Michal H.; Allers, Lee; Salemi, Michelle; Phinney, Brett S.; Johansen, Terje; Deretić, Vojo

doi:10.1016/j.molcel.2018.03.009

Cited by 207 publications

(261 citation statements)

References 57 publications

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“…We found that during lysosomal damage MTOR is inactivated and that it translocates from the lysosomal membrane to the cytosol, similar to what happens during starvation [1]. Cytosolic lectins termed galectins, recognize membrane damage by binding to lumenal glycans upon their exposure to the cytosol as a consequence of endomembrane damage.…”

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confidence: 61%

Galectins control MTOR and AMPK in response to lysosomal damage to induce autophagy

et al. 2018

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The Ser/Thr protein kinase MTOR (mechanistic target of rapamycin kinase) regulates cellular metabolism and controls macroautophagy/autophagy. Autophagy has both metabolic and quality control functions, including recycling nutrients at times of starvation and removing dysfunctional intracellular organelles. Lysosomal damage is one of the strongest inducers of autophagy, and yet mechanisms of its activation in response to lysosomal membrane damage are not fully understood. Our recent study has uncovered a new signal transduction system based on cytosolic galectins that elicits autophagy by controlling master regulators of metabolism and autophagy, MTOR and AMPK, in response to lysosomal damage. Thus, intracellular galectins are not, as previously thought, passive tags recognizing damage to guide selective autophagy receptors, but control the activation state of AMPK and MTOR in response to endomembrane damage. Abbreviations: MTOR: mechanistic target of rapamycin kinase; AMPK: AMP-activated protein kinase / Protein Kinase AMP-Activated; SLC38A9: Solute Carrier Family 38 Member 9; APEX2: engineered ascorbate peroxidase 2; RRAGA/B: Ras Related GTP Binding A or B; LAMTOR1: Late Endosomal/Lysosomal Adaptor, MAPK and MTOR Activator 1; LGALS8: Lectin, Galactoside-Binding, Soluble, 8 / Galectin 8; LGALS9: Lectin, Galactoside-Binding, Soluble, 9 / Galectin 9; TAK1: TGF-Beta Activated Kinase 1 / Mitogen-Activated Protein Kinase Kinase Kinase 7 (MAP3K7); STK11/LKB1: Serine/Threonine Kinase 11 / Liver Kinase B1; ULK1: Unc-51 Like Autophagy Activating Kinase 1.

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confidence: 61%

Galectins control MTOR and AMPK in response to lysosomal damage to induce autophagy

et al. 2018

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“…As a member of lectin family, LGALS8 (galectin‐8) plays key roles in various cellular processes, such as autophagy, cytoskeletal rearrangement, immunity and inflammation, as well as tumour progression . LGALS8 can recognize lysosome damage and promote autophagy through inhibiting mTOR activity . Remarkably, LGALS8 may serve as prognostic biomarkers in cancers.…”

Section: Discussionmentioning

confidence: 99%

A risk signature with four autophagy‐related genes for predicting survival of glioblastoma multiforme

Wang

Zhao

Xiao

et al. 2020

J Cellular Molecular Medi

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Glioblastoma multiforme (GBM) is a devastating brain tumour without effective treatment. Recent studies have shown that autophagy is a promising therapeutic strategy for GBM. Therefore, it is necessary to identify novel biomarkers associated with autophagy in GBM. In this study, we downloaded autophagy-related genes from Human Autophagy Database (HADb) and Gene Set Enrichment Analysis (GSEA) website. Least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis were performed to identify genes for constructing a risk signature. A nomogram was developed by integrating the risk signature with clinicopathological factors. Time-dependent receiver operating characteristic (ROC) curve and calibration plot were used to evaluate the efficiency of the prognostic model. Finally, four autophagy-related genes (DIRAS3, LGALS8, MAPK8 and STAM)were identified and were used for constructing a risk signature, which proved to be an independent risk factor for GBM patients. Furthermore, a nomogram was developed based on the risk signature and clinicopathological factors (IDH1 status, age and history of radiotherapy or chemotherapy). ROC curve and calibration plot suggested the nomogram could accurately predict 1-, 3-and 5-year survival rate of GBM patients.For function analysis, the risk signature was associated with apoptosis, necrosis, immunity, inflammation response and MAPK signalling pathway. In conclusion, the risk signature with 4 autophagy-related genes could serve as an independent prognostic factor for GBM patients. Moreover, we developed a nomogram based on the risk signature and clinical traits which was validated to perform better for predicting 1-, 3-and 5-year survival rate of GBM. K E Y W O R D Sautophagy, glioblastoma multiform, nomogram, prognosis, risk signature

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“…M. tuberculosis strains deficient in ESX-1 or PDIM synthesis show reduced galectin-3 or galectin-8 recruitment to intracellular sites of infection[23,24,33,34]. If the endosomal membrane is damaged, cytosolic galectins bind to lumenal β-galactoside-containing glycans that become exposed on damaged vesicles, and can be visualized by immunofluorescence microscopy[23,24,33–36]. Differing from the role of ESX-1 in phagosomal permeabilization during M. tuberculosis and M. marinum infection, the involvement of M. marinum PDIM in this process has not been demonstrated.…”

Section: Resultsmentioning

confidence: 99%

Mycobacterium marinumphthiocerol dimycocerosates enhance macrophage phagosomal permeabilization and membrane damage

Osman

Pagán

Shanahan

et al. 2020

Preprint

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17 18 Phthiocerol dimycocerosates (PDIMs) are a class of mycobacterial lipids that 19 promote virulence in Mycobacterium tuberculosis and Mycobacterium marinum. It 20 has recently been shown that PDIMs work in concert with the M. tuberculosis Type 21 VII secretion system ESX-1 to permeabilize the phagosomal membranes of infected 22 macrophages. As the zebrafish-M. marinum model of infection has revealed the 23 critical role of PDIM at the host-pathogen interface, we set to determine if PDIMs 24 contributed to phagosomal permeabilization in M. marinum. Using an ΔmmpL725 mutant defective in PDIM transport, we find the PDIM-ESX-1 interaction to be 26 conserved in an M. marinum macrophage infection model. However, we find PDIM 27 and ESX-1 mutants differ in their degree of defect, with the PDIM mutant retaining 28 more membrane damaging activity. Using an in vitro hemolysis assay-a common 29 surrogate for cytolytic activity, we find that PDIM and ESX-1 differ in their 30 contributions: the ESX-1 mutant loses hemolytic activity while PDIM retains it. Our 31 observations confirm the involvement of PDIMs in phagosomal permeabilization in 32 M. marinum infection and suggest that PDIM enhances the membrane disrupting 33 activity of pathogenic mycobacteria and indicates that the role they play in damaging 34 phagosomal and red blood cell membranes may differ.

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Galectins Control mTOR in Response to Endomembrane Damage

Cited by 207 publications

References 57 publications

Galectins control MTOR and AMPK in response to lysosomal damage to induce autophagy

Galectins control MTOR and AMPK in response to lysosomal damage to induce autophagy

A risk signature with four autophagy‐related genes for predicting survival of glioblastoma multiforme

Mycobacterium marinumphthiocerol dimycocerosates enhance macrophage phagosomal permeabilization and membrane damage

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