G3BP1 tethers the TSC complex to lysosomes and suppresses mTORC1 in the absence of stress granules

2020 ◽  
Author(s):  
Mirja T. Prentzell ◽  
Ulrike Rehbein ◽  
Marti Cadena Sandoval ◽  
Ann-Sofie De Meulemeester ◽  
Ralf Baumeister ◽  
...  
Keyword(s):  
Epileptiform Activity ◽  
Stress Granules ◽  
List Type ◽  
Protein Assemblies ◽  
Core Component ◽  
Cellular Survival ◽  
Mechanistic Target Of Rapamycin ◽  
Mtorc1 Signaling ◽  
Signaling Axis ◽  
Bona Fide

SummaryG3BP1 (Ras GTPase-activating protein-binding protein 1) is widely recognized as a core component of stress granules (SG), non-membranous RNA-protein-assemblies required for cellular survival under stress. We report that in the absence of SG, G3BP1 acts as lysosomal anchor of the Tuberous Sclerosis Complex (TSC) protein complex. By tethering the TSC complex to lysosomes, G3BP1 suppresses signaling through the metabolic master regulator mTORC1 (mechanistic target of rapamycin complex 1). Like the known TSC complex subunits, G3BP1 suppresses phenotypes related to mTORC1 hyperactivity in the context of tumors and neuronal dysfunction. Thus, G3BP1 is not only a core component of SG but also a key element of lysosomal TSC-mTORC1 signaling.HighlightsThe bona fide stress granule component G3BP1 is a key element of the TSC-mTORC1 signaling axis.tethers the TSC complex to lysosomes.prevents mTORC1 hyperactivation by metabolic stimuli.suppresses mTORC1-driven cancer cell motility and epileptiform activity.Graphical Abstract

scholarly journals mTORC1 Crosstalk With Stress Granules in Aging and Age-Related Diseases

2021 ◽  
Vol 2 ◽  
Author(s):  
Marti Cadena Sandoval ◽  
Alexander Martin Heberle ◽  
Ulrike Rehbein ◽  
Cecilia Barile ◽  
José Miguel Ramos Pittol ◽  
...  
Keyword(s):  
Growth Factor ◽  
Genomic Instability ◽  
Dynamic Process ◽  
Stress Granules ◽  
Telomere Shortening ◽  
Cellular Survival ◽  
Mechanistic Target Of Rapamycin ◽  
Age Related ◽  
Stress Signals ◽  
Complex Signaling

The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a master regulator of metabolism and aging. A complex signaling network converges on mTORC1 and integrates growth factor, nutrient and stress signals. Aging is a dynamic process characterized by declining cellular survival, renewal, and fertility. Stressors elicited by aging hallmarks such as mitochondrial malfunction, loss of proteostasis, genomic instability and telomere shortening impinge on mTORC1 thereby contributing to age-related processes. Stress granules (SGs) constitute a cytoplasmic non-membranous compartment formed by RNA-protein aggregates, which control RNA metabolism, signaling, and survival under stress. Increasing evidence reveals complex crosstalk between the mTORC1 network and SGs. In this review, we cover stressors elicited by aging hallmarks that impinge on mTORC1 and SGs. We discuss their interplay, and we highlight possible links in the context of aging and age-related diseases.

scholarly journals Norovirus infection results in assembly of virus-specific G3BP1 granules and evasion of eIF2α signaling

2018 ◽  
Author(s):  
Michèle Brocard ◽  
Valentina Iadevaia ◽  
Philipp Klein ◽  
Belinda Hall ◽  
Glenys Lewis ◽  
...  
Keyword(s):  
Host Cell ◽  
Rna Binding ◽  
Viral Gene Expression ◽  
Stress Granules ◽  
Viral Gene ◽  
Murine Norovirus ◽  
Initiation Factors ◽  
Protein Synthesis Machinery ◽  
Signaling Axis ◽  
Efficient Replication

ABSTRACTDuring viral infection, the accumulation of RNA replication intermediates or viral proteins imposes major stress on the host cell. In response, cellular stress pathways can rapidly impose defence mechanisms by shutting off the protein synthesis machinery, which viruses depend on, and triggering the accumulation of mRNAs into stress granules to limit the use of energy and nutrients. Because this threatens viral gene expression, viruses need to evade these pathways to propagate. Human norovirus is responsible for gastroenteritis outbreaks worldwide. Previously we showed that murine norovirus (MNV) regulates the activity of eukaryotic initiation factors (eIFs). Here we examined how MNV interacts with the eIF2α signaling axis controlling translation and stress granules accumulation. We show that while MNV infection represses host cell translation, it results in the assembly of virus-specific granules rather than stress granules. Further mechanistic analyses revealed that eIF2α signaling is uncoupled from translational stalling. Moreover the interaction of the RNA-binding protein G3BP1 with viral factors together with a redistribution of its cellular interacting partners could explain norovirus evasion of stress granules assembly. These results identify novel strategies by which norovirus ensure efficient replication propagation by manipulating the host stress response.

scholarly journals 005 Electroclinical characteristics of autoimmune encephalitis as outcome biomarkers

2019 ◽  
Vol 90 (e7) ◽  
pp. A2.2-A2
Author(s):  
Robb Wesselingh ◽  
James Broadley ◽  
Chris Kyndt ◽  
Katherine Buzzard ◽  
Terence O’Brien ◽  
...  
Keyword(s):  
Epileptiform Activity ◽  
Autoimmune Encephalitis ◽  
List Type ◽  
Predictive Values ◽  
Nmda Receptor Encephalitis ◽  
Prolonged Duration ◽  
Eeg Changes ◽  
Drug Resistant Epilepsy ◽  
Objective Description

IntroductionSeizures are a common characteristic of Autoimmune encephalitis (AIE). The use of the electroclinical characteristics to assist in the diagnosis of AIE has been explored1 however use of specific electroencephalogram (EEG) changes has not been examined with regards to outcome prediction.MethodsPatients with AIE were recruited retrospectively across 4 hospitals in Victoria. Clinical Data was collected during admission and at final follow-up. EEGs of patients were reviewed using an objective proforma. Associations between EEG biomarkers and clinical outcomes were demonstrated using logistic regression modelling.ResultsWe recruited 88 patients with AIE and available EEGs. Presence of rhythmic delta, superimposed fast activity and an abnormal background were significantly more common in N-methyl-D-aspartame receptor (NMDAR) antibody associated AIE patients (p<0.05). ICU admission was associated with rhythmic delta epileptiform activity (OR 3.25, p=0.046), sharp elements in the EEG abnormality (OR 3.55, p=0.05), and an abnormal background rhythm (OR 3.56, p=0.03). Development of drug resistant epilepsy was associated with prolonged duration of abnormality on EEG (OR 11.99, p=0.013), and sharp elements in the EEG abnormality (OR 7.29, p=0.02).ConclusionWe have identified EEG biomarkers that differentiate NMDAR AIE from other subtypes, and likely represents an objective description of extreme delta brush which has previously been described in NMDAR AIE.2 We have also demonstrated biomarkers associated with important outcomes that can be used to help guide treatment and prognosis.ReferencesLimotai C, Denlertchaikul C, Saraya AW, Jirasakuldej S. Predictive values and specificity of electroencephalographic findings in autoimmune encephalitis diagnosis. Epilepsy Behav 2018;84:29–36.Veciana M, Becerra JL, Fossas P, Muriana D, Sansa G, Santamarina E, et al. EEG extreme delta brush: An ictal pattern in patients with anti-NMDA receptor encephalitis. Epilepsy Behav 2015;49:280–5.

scholarly journals Functional Redundancy between β1 and β3 Integrin in Activating the IR/Akt/mTORC1 Signaling Axis to Promote ErbB2-Driven Breast Cancer

Cell Reports ◽  
2019 ◽  
Vol 29 (3) ◽  
pp. 589-602.e6 ◽  
Author(s):  
Tung Bui ◽  
Jonathan Rennhack ◽  
Stephanie Mok ◽  
Chen Ling ◽  
Marco Perez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Functional Redundancy ◽  
Mtorc1 Signaling ◽  
Signaling Axis ◽  
Β3 Integrin

scholarly journals Reciprocal Regulation between Primary Cilia and mTORC1

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 711 ◽  
Author(s):  
Yandong Lai ◽  
Yu Jiang
Keyword(s):  
Primary Cilia ◽  
Critical Role ◽  
Inhibitory Effect ◽  
Reciprocal Regulation ◽  
Quiescent Cells ◽  
Mechanistic Target Of Rapamycin ◽  
Tumor Suppressor Proteins ◽  
Mtorc1 Signaling ◽  
Liver Kinase B1 ◽  
Amp Activated Protein Kinase

In quiescent cells, primary cilia function as a mechanosensor that converts mechanic signals into chemical activities. This unique organelle plays a critical role in restricting mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is essential for quiescent cells to maintain their quiescence. Multiple mechanisms have been identified that mediate the inhibitory effect of primary cilia on mTORC1 signaling. These mechanisms depend on several tumor suppressor proteins localized within the ciliary compartment, including liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK), polycystin-1, and polycystin-2. Conversely, changes in mTORC1 activity are able to affect ciliogenesis and stability indirectly through autophagy. In this review, we summarize recent advances in our understanding of the reciprocal regulation of mTORC1 and primary cilia.

scholarly journals STAT1 maintains naïve CD8 + T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis

2021 ◽  
Vol 7 (36) ◽  
Author(s):  
Yoon-Chul Kye ◽  
Gil-Woo Lee ◽  
Sung-Woo Lee ◽  
Young-Jun Ju ◽  
Hee-Ok Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Cd8 T Cell ◽  
Type I ◽  
Type I Ifn ◽  
Mtorc1 Signaling ◽  
Cell Quiescence ◽  
Signaling Axis

scholarly journals Structure of S. pombe telomerase protein Pof8 C-terminal domain is an xRRM conserved among LARP7 proteins

2019 ◽  
Author(s):  
Ritwika Basu ◽  
Catherine D. Eichhorn ◽  
Ryan Cheng ◽  
Juli Feigon
Keyword(s):  
Fission Yeast ◽  
Rna Binding ◽  
List Type ◽  
Core Component ◽  
Nmr Studies ◽  
Structure Comparison ◽  
Eukaryotic Chromosome ◽  
Terminal Domain ◽  
Yeast Telomerase ◽  
Definition Of

AbstractLa related proteins group 7 (LARP7) are a class of RNA chaperones that bind the 3’ends of RNA and are constitutively associated with their specific target RNAs. In metazoa, Larp7 binds to the long non-coding 7SK RNA as a core component of the 7SK RNP, a major regulator of eukaryotic transcription. In ciliates, a LARP7 protein (p65 in Tetrahymena) is a core component of telomerase, an essential ribonucleoprotein complex that maintains the DNA length at eukaryotic chromosome ends. p65 is important for the ordered assembly of telomerase RNA (TER) with telomerase reverse transcriptase (TERT). Although a LARP7 as a telomerase holoenzyme component was initially thought to be specific to ciliate telomerases, Schizosaccharomyces pombe Pof8 was recently identified as a LARP7 protein and a core component of fission yeast telomerase essential for biogenesis. There is also evidence that human Larp7 associates with telomerase. LARP7 proteins have conserved N-terminal La motif and RRM1 (La module) and C-terminal RRM2 with specific RNA substrate recognition attributed to RRM2, first structurally characterized in p65 as an atypical RRM named xRRM. Here we present the X-ray crystal structure and NMR studies of S. pombe Pof8 RRM2. Sequence and structure comparison of Pof8 RRM2 to p65 and hLarp7 xRRMs reveals conserved features for RNA binding with the main variability in the length of the non-canonical helix α3. This study shows that Pof8 has conserved xRRM features, providing insight into TER recognition and the defining characteristics of the xRRM.HighlightsThe structure of the S. pombe LARP7 Pof8 C-terminal domain is an xRRM.Ciliates, human, and fission yeast contain LARP7 proteins with xRRMs involved in telomerase biogenesis.With three examples of xRRM structures, we refine the definition of xRRM.

scholarly journals Drosophila PDGF/VEGF signaling from muscles to hepatocyte-like cells protects against obesity

2019 ◽  
Author(s):  
Arpan C. Ghosh ◽  
Sudhir G. Tattikota ◽  
Yifang Liu ◽  
Aram Comjean ◽  
Yanhui Hu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Synthesis ◽  
Rapid Expansion ◽  
List Type ◽  
Tissue Lipid ◽  
Mature Adult ◽  
Signaling Axis ◽  
Organ Specific ◽  
Lipid Stores ◽  
Multicellular Organisms

AbstractPDGF/VEGF ligands regulate a plethora of biological processes in multicellular organisms via autocrine, paracrine and endocrine mechanisms. Here, we investigated organ-specific roles of Drosophila PDGF/VEGF-like factors (Pvfs). We combine genetic approaches and single-nuclei sequencing to demonstrate that muscle-derived Pvf1 signals to the Drosophila hepatocyte-like cells/oenocytes to suppress lipid synthesis by activating the Pi3K/Akt1/mTOR signaling cascade in the oenocytes. Additionally, we show that this signaling axis regulates the rapid expansion of adipose tissue lipid stores observed in newly eclosed flies. Flies emerge after pupation with limited adipose tissue lipid stores and lipid levels are progressively restored via lipid synthesis. We find that pvf1 expression in the adult muscle increase rapidly during this stage and that muscle-to-oenocyte Pvf1 signaling inhibits restoration of adipose tissue lipid stores as the process reaches completion. Our findings provide the first evidence in a metazoan of a PDGF/VEGF ligand acting as a myokine that regulates systemic lipid homeostasis by activating mTOR in hepatocyte-like cells.HighlightsMuscle specific Pvf1 protects mature adult flies from obesitySingle-nuclei RNA sequencing reveals that PvR, the receptor for Pvf1, is highly expressed in the Drosophila hepatocyte-like cells/oenocytes.PvR is required specifically in oenocytes to protect adult flies from obesityMuscle-to-oenocyte Pvf1 signaling activates PvR/Pi3K/Akt1/mTOR in the oenocytes to suppress lipid synthesisMuscle-derived Pvf1 helps terminate the rapid expansion of adipose tissue lipid stores in newly eclosed flies

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