GRASP55 and UPR Control Interleukin-1β Aggregation and Secretion

Chirițoiu, Marioara; Brouwers, Nathalie; Turacchio, Gabriele; Pirozzi, Marinella; Malhotra, Vivek

doi:10.1016/j.devcel.2019.02.011

Cited by 48 publications

(58 citation statements)

References 45 publications

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“…These situations can include viral infection (Clavarino et al, 2012b), exposure to high levels of fatty acids during pathogenesis, oxidative stress during inflammation or amino acids starvation, mediated by amino acid degrading enzymes, like Arginase 1 or IDO, which are induced during infection or cancer development (Claudio et al, 2013, Munn et al, 2004. Importantly we could also show, that in contrast to macrophages, PERK and ISR induction are not necessary for DCs to drive the transcription of pro-inflammatory cytokines in response to TRIF or MAVs dependent-signaling (Abdel-Nour et al, 2019) nor the secretion of IL-1β (Chiritoiu et al, 2019).…”

Section: Discussionmentioning

confidence: 61%

“…We found that mRNA translation in DCs, differently to what has been shown during chronic ISR , is mediated despite high p-eIF2α levels by an eIF4F-dependent mechanism. We also found that primary DCs, conversely to macrophages, do not rely on eIF2α phosphorylation to activate cytokines transcription nor IL-1β secretion in response to MAMPs (Abdel-Nour et al, 2019), (Chiritoiu et al, 2019). Importantly, GADD34 antagonizes PERK activity to maintain functional protein synthesis levels in non-activated DCs.…”

Section: Introductionmentioning

confidence: 70%

“…Interleukin-1 beta (IL-1β) secretion in BMM. PERK was proposed to control the caspase-1-dependent proteolysis of pro-to mature-IL-1β, while IRE1a to keep mature IL-1β soluble to allow its secretion (Chiritoiu et al, 2019). LPS-activated WT and PERKΔK-DCs were co-stimulated with ATP to promote conversion of cytosolic pro-to mature IL-1β and its secretion (Fig.…”

Section: Importance Of the Isr For Innate Receptors Signaling In Dcsmentioning

confidence: 99%

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Developmentally regulated PERK activity renders dendritic cells insensitive to subtilase cytotoxin-induced integrated stress response

Pierre

Mendes

Gigan

et al. 2020

Preprint

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In stressed cells, phosphorylation of eukaryotic initiation factor 2α (eIF2α) controls transcriptome-wide changes in mRNA translation and gene expression known as the integrated stress response (ISR). We show here that dendritic cells (DCs) display unusually high eIF2α phosphorylation, which is mostly caused by a developmentally regulated activation of the ER kinase PERK (EIF2AK3). Despite high p-eIF2α levels, differentiated DCs display active protein synthesis and no signs of a chronic ISR. eIF2α phosphorylation does not majorly impact DC differentiation nor cytokines production. It is however important to adapt protein homeostasis to the variations imposed on DCs by the immune or physiological contexts. This biochemical specificity prevents translation arrest and expression of the transcription factor ATF4 during ER-stress induction by subtilase cytotoxin or upon DC stimulation with bacterial lipopolysaccharides. This is also exemplified by the influence of the actin cytoskeleton dynamics on eIF2α phosphorylation and the migratory deficit observed in PERK-deficient DCs.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 70%

Section: Importance Of the Isr For Innate Receptors Signaling In Dcsmentioning

confidence: 99%

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Developmentally regulated PERK activity renders dendritic cells insensitive to subtilase cytotoxin-induced integrated stress response

Pierre

Mendes

Gigan

et al. 2020

Preprint

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“…More recently, the export of cytoplasmic enzyme superoxide dismutase 1 (SOD1) was reported to follow the same pathway as Acb1, and both depend on a di-acidic motif (Cruz-Garcia et al, 2017). The release of IL-1ß, however, does not appear to have a unifying theme, and depending on the cell type or stimulus different mechanisms have been proposed that include pore formation via gasdermin D, autophagymediated, and via an intermediate membrane compartment (Rubartelli et al, 1990;Andrei et al, 2004;Dupont et al, 2011;Liu et al, 2016;Chiritoiu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species (ROS) triggers unconventional secretion of antioxidants and Acb1

Cruz-García

Brouwers

Malhotra

et al. 2019

Preprint

Self Cite

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Nutrient deprivation triggers the release of signal-sequence-lacking antioxidant superoxide dismutase 1 (SOD1). We now report that secreted SOD1 is functionally active and accompanied by export of other antioxidant enzymes such as thioredoxins, (Trx1 and Trx2) and peroxiredoxin Ahp1. Our data reveal that starvation increases mitochondrial activity, which generates higher, but non-toxic, levels of reactive oxygen species (ROS). Inhibiting mitochondrial activity or ROS prevents antioxidants secretion. We suggest that in response to ROS production that can permeate the plasma membrane, the cells respond by secreting antioxidants to prevent ROSmediated damage in the extracellular space. These findings provide an understanding of why cells secrete signal sequence lacking antioxidant enzymes in response to starvation.

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“…GRASP can interact directly with the C-terminus of the Transforming Growth Factorα (TGF-α) and with several members of the p24 family, facilitating the conventional protein secretion pathway [13,14]. GRASPs also have a direct and essential role in the unconventional secretion of a large number of proteins, such as: (1) the soluble acyl-coenzyme A binding protein (ACBP) in Dictyostelium [15], Saccharomyces cerevisiae and Pichia pastoris [16,17], (2) the Golgi bypass of αPS1 integrin during the stage 10B of Drosophila embryogenesis [18], (3) the mutant ΔF508 of the cystic fibrosis transmembrane conductance regulator (CFTR) in an ER stress situation [19], (4) in the secretion of IL1-β [20], among others [21,22]. GRASP is apparently also required for the export of non-protein molecules.…”

Section: Introductionmentioning

confidence: 99%

Conformational flexibility of GRASP protein and its constituent PDZ subdomains reveals structural basis of its promiscuous interactome

Lfs

Mrb

Judge

et al. 2019

Preprint

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Significance Statement:Golgi Reassembly and Stacking Proteins (GRASPs) play pivotal roles in the maintenance of Golgi structure as well as in unconventional protein secretion. Their broad network of interactions is mainly sustained by the two-PDZ domains located in the N-terminal portion of the protein. The asymmetry of the PDZ domains in terms of number and diversity of interacting partners has been long recognized, but the molecular determinants of that asymmetry remains largely unknown. The biophysical data presented here provide a firm basis for understanding why PDZ1 behaves differently to PDZ2 in solution, despite their similar 3D structures.Furthermore, we propose that PDZ2 assist ligand binding to PDZ1, by means of conformational stabilization. AbstractThe Golgi complex is a central component of the secretory pathway, responsible for several critical cellular functions in eukaryotes. The complex is organized by the Golgi matrix, which includes the Golgi Reassembly and Stacking Proteins (GRASPs), which participate in cisternae stacking and lateral linkage in vertebrates. GRASPs also have critical roles in other processes, with an unusual ability to interact with several different protein binding partners. The conserved N-terminus of the GRASP family includes two PDZ domains. Previous crystallographic studies of orthologues suggest that PDZ1 and PDZ2 have similar conformations and secondary structure content, however PDZ1 alone mediates nearly all the interactions between GRASPs and their binding partners. In this work, NMR, Synchrotron-Radiation Circular Dichroism and Molecular Dynamics were used to examine the structure, flexibility and stability of the two constituent PDZ domains. GRASP PDZs are structured in an unusual β 3 α 1 β 4 β 5 α 2 β 6 β 1 β 2 secondary structural arrangement and NMR data indicates that the PDZ1 binding pocket is formed by a stable β 2 -strand and a more flexible and unstable α 2 -helix, suggesting an explanation for the higher PDZ1 promiscuity. The conformational free energy profiles of the two PDZ domains were calculated using Molecular Dynamics simulations. The data suggest that, after binding, the protein partner significantly reduces the conformational space that GRASPs can access by stabilizing one particular conformation, in a partner-dependent fashion.The structural flexibility of PDZ1, modulated by PDZ2, and the coupled, coordinated movement between the two PDZs enable GRASPs to interact with multiple partners, allowing them to function as promiscuous, multitasking proteins.

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GRASP55 and UPR Control Interleukin-1β Aggregation and Secretion

Cited by 48 publications

References 45 publications

Developmentally regulated PERK activity renders dendritic cells insensitive to subtilase cytotoxin-induced integrated stress response

Developmentally regulated PERK activity renders dendritic cells insensitive to subtilase cytotoxin-induced integrated stress response

Reactive oxygen species (ROS) triggers unconventional secretion of antioxidants and Acb1

Conformational flexibility of GRASP protein and its constituent PDZ subdomains reveals structural basis of its promiscuous interactome

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